chr10-43126673-C-A

Variant names:

• chr10-43126673-C-A
• rs201576838
• NM_020975.6:c.3138C>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_020975.6(RET):​c.3138C>A​(p.Ala1046Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,042 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1046A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.82
• Publications: 0 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 10-43126673-C-A is Benign according to our data. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126673-C-A is described in CliVar as Likely_benign. Clinvar id is 184537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000233 (34/1461844) while in subpopulation AMR AF = 0.000335 (15/44724). AF 95% confidence interval is 0.000206. There are 0 homozygotes in GnomAdExome4. There are 18 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.3138C>A	p.Ala1046Ala	synonymous_variant	Exon 19 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.3138C>A	p.Ala1046Ala	synonymous_variant	Exon 19 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251462 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727214

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

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

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

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111992

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74414

African (AFR) AF: 0.00 AC: 0 AN: 41524

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Dec 29, 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. -

May 18, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Benign:1

Apr 26, 2018

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. -

RET-related disorder Benign:1

Oct 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.1
DANN	Benign	0.69
PhyloP100		2.8
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: rs201576838; hg19: chr10-43622121;