10-43111239-A-G

Variant names:

• chr10-43111239-A-G
• rs1800860
• NM_020975.6:c.1296A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020975.6(RET):​c.1296A>G​(p.Ala432Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.7 in 1,613,918 control chromosomes in the GnomAD database, including 397,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A432A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.74 (42545 hom., cov: 33)
  • Exomes 𝑓: 0.70 (355311 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 0.314
• Publications: 74 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 10-43111239-A-G is Benign according to our data. Variant chr10-43111239-A-G is described in ClinVar as Benign. ClinVar VariationId is 95995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.314 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.854 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.1296A>G	p.Ala432Ala	synonymous_variant	Exon 7 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1296A>G	p.Ala432Ala	synonymous_variant	Exon 7 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.742 AC: 112874 AN: 152048 Hom.: 42487 Cov.: 33

Gnomad AFR AF: 0.861

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.811

Gnomad SAS AF: 0.745

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.690

Gnomad OTH AF: 0.760

GnomAD2 exomes AF: 0.696 AC: 174813 AN: 251204 AF XY: 0.701

Gnomad AFR exome AF: 0.864

Gnomad AMR exome AF: 0.544

Gnomad ASJ exome AF: 0.674

Gnomad EAS exome AF: 0.799

Gnomad FIN exome AF: 0.695

Gnomad NFE exome AF: 0.691

Gnomad OTH exome AF: 0.701

GnomAD4 exome AF: 0.696 AC: 1016689 AN: 1461752 Hom.: 355311 Cov.: 70 AF XY: 0.697 AC XY: 506674 AN XY: 727186

African (AFR) AF: 0.872 AC: 29210 AN: 33480

American (AMR) AF: 0.561 AC: 25107 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 17550 AN: 26136

East Asian (EAS) AF: 0.811 AC: 32191 AN: 39698

South Asian (SAS) AF: 0.740 AC: 63800 AN: 86258

European-Finnish (FIN) AF: 0.693 AC: 36963 AN: 53324

Middle Eastern (MID) AF: 0.797 AC: 4595 AN: 5768

European-Non Finnish (NFE) AF: 0.687 AC: 764287 AN: 1111972

Other (OTH) AF: 0.712 AC: 42986 AN: 60392

GnomAD4 genome AF: 0.743 AC: 112996 AN: 152166 Hom.: 42545 Cov.: 33 AF XY: 0.745 AC XY: 55452 AN XY: 74384

African (AFR) AF: 0.861 AC: 35772 AN: 41526

American (AMR) AF: 0.677 AC: 10355 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2393 AN: 3470

East Asian (EAS) AF: 0.811 AC: 4188 AN: 5162

South Asian (SAS) AF: 0.746 AC: 3600 AN: 4826

European-Finnish (FIN) AF: 0.695 AC: 7359 AN: 10582

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.690 AC: 46887 AN: 67996

Other (OTH) AF: 0.764 AC: 1613 AN: 2112

Alfa AF: 0.705 Hom.: 85141

Bravo AF: 0.743

Asia WGS AF: 0.788 AC: 2741 AN: 3478

EpiCase AF: 0.706

EpiControl AF: 0.703

ClinVar

Significance: Benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Mar 23, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 12, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This "variant" is a RefSeq error. G at this position is the major allele with an allele frequency of 70% in gnomAD (http://gnomad.broadinstitute.org/variant/10- 43606687-A-G). -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Pheochromocytoma Benign:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia, type 2 Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 06, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia type 2B Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Benign:2

Nov 18, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Jan 01, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1 -

Hirschsprung disease, susceptibility to, 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Renal hypodysplasia/aplasia 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Multiple endocrine neoplasia type 2A Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.8
DANN	Benign	0.37
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs1800860; hg19: chr10-43606687; COSMIC: COSV60686810; COSMIC: COSV60686810;