rs1799939

Positions:

• chr10-43114671-G-A
• chr10-43114671-G-C
• chr10-43114671-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_020975.6(RET):​c.2071G>A​(p.Gly691Ser) variant causes a missense change. The variant allele was found at a frequency of 0.184 in 1,612,242 control chromosomes in the GnomAD database, including 29,287 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.17 (2471 hom., cov: 31)
  • Exomes 𝑓: 0.19 (26816 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:21 O:1
• Conservation: PhyloP100: 4.41

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005253911).
• BP6: Variant 10-43114671-G-A is Benign according to our data. Variant chr10-43114671-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24934.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=1, Benign=13, Uncertain_significance=1}. Variant chr10-43114671-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.2071G>A	p.Gly691Ser	missense_variant	11/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2071G>A	p.Gly691Ser	missense_variant	11/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25745 AN: 151742 Hom.: 2472 Cov.: 31

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.210 AC: 52572 AN: 250098 Hom.: 6336 AF XY: 0.208 AC XY: 28214 AN XY: 135328

Gnomad AFR exome AF: 0.0983

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.195

Gnomad EAS exome AF: 0.116

Gnomad SAS exome AF: 0.255

Gnomad FIN exome AF: 0.218

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.185 AC: 270502 AN: 1460382 Hom.: 26816 Cov.: 36 AF XY: 0.187 AC XY: 135943 AN XY: 726526

Gnomad4 AFR exome AF: 0.0963

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.0943

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.212

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.180

GnomAD4 genome AF: 0.170 AC: 25747 AN: 151860 Hom.: 2471 Cov.: 31 AF XY: 0.173 AC XY: 12841 AN XY: 74188

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.243

Gnomad4 FIN AF: 0.230

Gnomad4 NFE AF: 0.182

Gnomad4 OTH AF: 0.179

Alfa AF: 0.180 Hom.: 3497

Bravo AF: 0.170

TwinsUK AF: 0.182 AC: 674

ALSPAC AF: 0.181 AC: 699

ESP6500AA AF: 0.103 AC: 455

ESP6500EA AF: 0.185 AC: 1587

ExAC AF: 0.202 AC: 24557

Asia WGS AF: 0.169 AC: 586 AN: 3478

EpiCase AF: 0.189

EpiControl AF: 0.194

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:21 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:8 Other:1

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 10, 2020	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 11, 2013	Gly691Ser in exon 11 of RET: This variant is not expected to have clinical signi ficance because it has been identified in 21% (276/1321) chromosomes from a broa d, though clinically and racially unspecified population (dbSNP rs1799939). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2016	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. -

Multiple endocrine neoplasia, type 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2021	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Multiple endocrine neoplasia type 2A Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 06, 2019	- -

Multiple endocrine neoplasia type 2B Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Pheochromocytoma Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hirschsprung disease, susceptibility to, 1 Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Renal hypodysplasia/aplasia 1 Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Multiple endocrine neoplasia Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Uncertain	0.42	T;.
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0053	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.21
Sift	Benign	0.18	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.062	B;B
Vest4		0.045
MPC		0.20
ClinPred		0.015	T
GERP RS		-1.1
Varity_R		0.039
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1799939; hg19: chr10-43610119; COSMIC: COSV60687096; COSMIC: COSV60687096;