chr10-43109125-G-A

Variant names:

• chr10-43109125-G-A
• rs373540097
• NM_020975.6:c.1158G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_020975.6(RET):​c.1158G>A​(p.Ala386Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A386A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 0.252
• Publications: 3 publications found

Genes affected

RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

RET Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 10-43109125-G-A is Benign according to our data. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095. Variant chr10-43109125-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 136095.
• BP7: Synonymous conserved (PhyloP=0.252 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.1158G>A	p.Ala386Ala	synonymous_variant	Exon 6 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1158G>A	p.Ala386Ala	synonymous_variant	Exon 6 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000414 AC: 104 AN: 250982 AF XY: 0.000420

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000271 AC: 396 AN: 1461598 Hom.: 0 Cov.: 33 AF XY: 0.000250 AC XY: 182 AN XY: 727122

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00788 AC: 206 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000132 AC: 147 AN: 1112006

Other (OTH) AF: 0.000596 AC: 36 AN: 60392

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74336

African (AFR) AF: 0.0000483 AC: 2 AN: 41424

American (AMR) AF: 0.000393 AC: 6 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.000581 Hom.: 0

Bravo AF: 0.000298

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Sep 21, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 21, 2018

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RET c.1158G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00041 in 250982 control chromosomes (gnomAD). The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1158G>A in individuals affected with Multiple Endocrine Neoplasia Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (1x) / likely benign (2x). Based on the evidence outlined above, the variant was classified as benign. -

Multiple endocrine neoplasia, type 2 Benign:2

Nov 14, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Oct 16, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Oct 20, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Renal hypodysplasia/aplasia 1 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Pheochromocytoma Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hirschsprung disease, susceptibility to, 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Multiple endocrine neoplasia type 2A Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RET: BP4, BP7 -

Multiple endocrine neoplasia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.7
DANN	Benign	0.66
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373540097; hg19: chr10-43604573;