rs1800860

Positions:

• chr10-43111239-A-G
• chr10-43111239-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020975.6(RET):​c.1296A>G​(p.Ala432=) 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 (★★).

• 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:21
• Conservation: PhyloP100: 0.314

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 95995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111239-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.1296A>G	p.Ala432=	synonymous_variant	7/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1296A>G	p.Ala432=	synonymous_variant	7/20	5	NM_020975.6	ENSP00000347942	P4

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

GnomAD3 exomes AF: 0.696 AC: 174813 AN: 251204 Hom.: 61725 AF XY: 0.701 AC XY: 95211 AN XY: 135828

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 SAS exome AF: 0.742

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

Gnomad4 AFR exome AF: 0.872

Gnomad4 AMR exome AF: 0.561

Gnomad4 ASJ exome AF: 0.671

Gnomad4 EAS exome AF: 0.811

Gnomad4 SAS exome AF: 0.740

Gnomad4 FIN exome AF: 0.693

Gnomad4 NFE exome AF: 0.687

Gnomad4 OTH exome AF: 0.712

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

Gnomad4 AFR AF: 0.861

Gnomad4 AMR AF: 0.677

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.811

Gnomad4 SAS AF: 0.746

Gnomad4 FIN AF: 0.695

Gnomad4 NFE AF: 0.690

Gnomad4 OTH AF: 0.764

Alfa AF: 0.698 Hom.: 58864

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:21

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 12, 2018	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). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Multiple endocrine neoplasia, type 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -

Multiple endocrine neoplasia type 2B Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Pheochromocytoma Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Hirschsprung disease, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Multiple endocrine neoplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.8
DANN	Benign	0.37

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

Publications

LitVar

Other links and lift over

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