rs2435351

Positions:

chr10-43100731-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020975.6(RET):c.337+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 1,583,280 control chromosomes in the GnomAD database, including 52,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3868 hom., cov: 31)

Exomes 𝑓: 0.25 ( 48375 hom. )

Consequence

RET
NM_020975.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 1.12

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 10-43100731-G-A is Benign according to our data. Variant chr10-43100731-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 95996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100731-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6 linkuse as main transcript	c.337+9G>A		intron_variant		ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.337+9G>A		intron_variant		5	NM_020975.6	ENSP00000347942	P4	P07949-1

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31729

AN:

151540

Hom.:

3864

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0949

Gnomad AMI

AF:

0.350

Gnomad AMR

AF:

0.260

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.258

Gnomad MID

AF:

0.261

Gnomad NFE

AF:

0.259

Gnomad OTH

AF:

0.212

GnomAD3 exomes

AF:

0.257

AC:

50491

AN:

196552

Hom.:

7063

AF XY:

0.258

AC XY:

27353

AN XY:

106116

show subpopulations

Gnomad AFR exome

AF:

0.0954

Gnomad AMR exome

AF:

0.356

Gnomad ASJ exome

AF:

0.241

Gnomad EAS exome

AF:

0.102

Gnomad SAS exome

AF:

0.303

Gnomad FIN exome

AF:

0.258

Gnomad NFE exome

AF:

0.259

Gnomad OTH exome

AF:

0.267

GnomAD4 exome

AF:

0.255

AC:

364788

AN:

1431622

Hom.:

48375

Cov.:

AF XY:

0.256

AC XY:

181424

AN XY:

709260

show subpopulations

Gnomad4 AFR exome

AF:

0.0896

Gnomad4 AMR exome

AF:

0.342

Gnomad4 ASJ exome

AF:

0.246

Gnomad4 EAS exome

AF:

0.0886

Gnomad4 SAS exome

AF:

0.302

Gnomad4 FIN exome

AF:

0.255

Gnomad4 NFE exome

AF:

0.260

Gnomad4 OTH exome

AF:

0.241

GnomAD4 genome

AF:

0.209

AC:

31738

AN:

151658

Hom.:

3868

Cov.:

AF XY:

0.212

AC XY:

15735

AN XY:

74094

show subpopulations

Gnomad4 AFR

AF:

0.0947

Gnomad4 AMR

AF:

0.260

Gnomad4 ASJ

AF:

0.246

Gnomad4 EAS

AF:

0.101

Gnomad4 SAS

AF:

0.292

Gnomad4 FIN

AF:

0.258

Gnomad4 NFE

AF:

0.259

Gnomad4 OTH

AF:

0.210

Alfa

AF:

0.243

Hom.:

1656

Bravo

AF:

0.207

Asia WGS

AF:

0.182

AC:

631

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 19, 2018	This variant is classified as benign because it has been identified in 36% (1044 7/29350) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs2435351). ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2014	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 12872262) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Renal hypodysplasia/aplasia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Multiple endocrine neoplasia type 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Aug 06, 2019

- -

Multiple endocrine neoplasia, type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Multiple endocrine neoplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2015

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

-0.82

CADD

Benign

DANN

Benign

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over