rs192489011

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_020975.6(RET):c.200G>A(p.Arg67His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,613,870 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00059 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00038 ( 5 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:13O:1

Conservation

PhyloP100: 0.0800

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068158507).

BP6

Variant 10-43100585-G-A is Benign according to our data. Variant chr10-43100585-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 41839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100585-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6 linkuse as main transcript	c.200G>A	p.Arg67His	missense_variant	2/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.200G>A	p.Arg67His	missense_variant	2/20	5	NM_020975.6	P4	P07949-1

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0141

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00112

AC:

280

AN:

251082

Hom.:

AF XY:

0.00107

AC XY:

145

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0123

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000380

AC:

556

AN:

1461600

Hom.:

Cov.:

AF XY:

0.000384

AC XY:

279

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00763

Gnomad4 SAS exome

AF:

0.000487

Gnomad4 FIN exome

AF:

0.000941

Gnomad4 NFE exome

AF:

0.0000998

Gnomad4 OTH exome

AF:

0.000712

GnomAD4 genome

AF:

0.000591

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0143

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000417

Hom.:

Bravo

AF:

0.000525

ExAC

AF:

0.00101

AC:

123

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 04, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 14, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 07, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2017	- -

Multiple endocrine neoplasia, type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 29, 2022	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 07, 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. -

Pheochromocytoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 04, 2018

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine 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

Jun 04, 2018

Renal hypodysplasia/aplasia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 04, 2018

Multiple endocrine neoplasia type 2A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Nov 10, 2022

- -

Multiple endocrine neoplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 04, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

Cadd

Benign

9.5

Dann

Benign

0.77

DEOGEN2

Benign

0.37

T;.;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.60

T;T;T

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.91

L;.;L

MutationTaster

Benign

0.93

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.47

N;.;N

REVEL

Benign

0.13

Sift

Benign

0.61

T;.;T

Sift4G

Benign

0.58

T;T;T

Polyphen

0.0020

B;.;B

Vest4

0.028

MVP

0.47

MPC

0.93

ClinPred

0.011

GERP RS

-0.21

Varity_R

0.026

gMVP

0.51

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