chr10-43106382-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020975.6(RET):​c.874G>A​(p.Val292Met) variant causes a missense change. The variant allele was found at a frequency of 0.000227 in 1,610,770 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00021 ( 4 hom. )

Consequence

RET
NM_020975.6 missense

Scores

12
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:11O:1

Conservation

PhyloP100: 6.73
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010467678).
BP6
Variant 10-43106382-G-A is Benign according to our data. Variant chr10-43106382-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24880.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=4, Likely_benign=7, not_provided=1}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000368 (56/152320) while in subpopulation EAS AF= 0.00946 (49/5182). AF 95% confidence interval is 0.00735. There are 1 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RETNM_020975.6 linkc.874G>A p.Val292Met missense_variant Exon 5 of 20 ENST00000355710.8 NP_066124.1 P07949-1A0A024R7T2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RETENST00000355710.8 linkc.874G>A p.Val292Met missense_variant Exon 5 of 20 5 NM_020975.6 ENSP00000347942.3 P07949-1

Frequencies

GnomAD3 genomes
AF:
0.000361
AC:
55
AN:
152202
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00924
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000625
AC:
154
AN:
246360
Hom.:
0
AF XY:
0.000612
AC XY:
82
AN XY:
133944
show subpopulations
Gnomad AFR exome
AF:
0.000125
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00700
Gnomad SAS exome
AF:
0.000360
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000539
Gnomad OTH exome
AF:
0.000496
GnomAD4 exome
AF:
0.000212
AC:
309
AN:
1458450
Hom.:
4
Cov.:
32
AF XY:
0.000218
AC XY:
158
AN XY:
725624
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.00378
Gnomad4 SAS exome
AF:
0.000441
Gnomad4 FIN exome
AF:
0.0000196
Gnomad4 NFE exome
AF:
0.0000621
Gnomad4 OTH exome
AF:
0.000647
GnomAD4 genome
AF:
0.000368
AC:
56
AN:
152320
Hom.:
1
Cov.:
33
AF XY:
0.000376
AC XY:
28
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00946
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000267
Hom.:
0
Bravo
AF:
0.000306
ExAC
AF:
0.000527
AC:
64
Asia WGS
AF:
0.00260
AC:
9
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:11Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:4Benign:2
Oct 01, 2017
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 07, 2017
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is denoted RET c.874G>A at the cDNA level, p.Val292Met (V292M) at the protein level, andresults in the change of a Valine to a Methionine (GTG>ATG). This variant was observed in at least one individual withpheochromocytoma and medullary thyroid cancer and four individuals with Hirschsprung disease (Castellone 2010, So2011, Ngo 2012). This variant has also been identified in 1/62 healthy East Asian individuals undergoing wholegenome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus theunaffected status of this individual may not be significant. RET Val292Met was observed at an allele frequency of0.624% (52/8336) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project,The 1000 Genomes Consortium 2015, Lek 2016).Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. RETVal292Met occurs at a position that is conserved across species and is located in the extracellular topological domainand cadherin domain (Garcia-Barcelo 2004). In silico analyses are inconsistent regarding the effect this variant mayhave on protein structure and function. Based on currently available evidence, it is unclear whether RET Val292Met isa pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Apr 12, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 03, 2021
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 04, 2017
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:2Other:1
Jun 19, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. This variant has been seen where an alternate explanation for disease was also identified (PMID: 21655256; 32989896). This variant does not segregate with disease in at least one family (PMID: 32989896). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 20039896). -

Mar 02, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Jul 16, 2021
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. -

Dec 02, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Multiple endocrine neoplasia type 2B Uncertain:1
Nov 21, 2018
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Pheochromocytoma Benign:1
Jun 04, 2018
Illumina Laboratory Services, Illumina
Significance: Likely 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). 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
Jun 04, 2018
Illumina Laboratory Services, Illumina
Significance: Likely 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). 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. -

Renal hypodysplasia/aplasia 1 Benign:1
Jun 04, 2018
Illumina Laboratory Services, Illumina
Significance: Likely 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). 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. -

Multiple endocrine neoplasia, type 2 Benign:1
Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Multiple endocrine neoplasia Benign:1
Jun 04, 2018
Illumina Laboratory Services, Illumina
Significance: Likely 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). 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. -

Hereditary cancer Benign:1
Jan 23, 2024
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.098
T
BayesDel_noAF
Uncertain
0.090
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.47
T;.;.
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.68
T;T;T
MetaRNN
Benign
0.010
T;T;T
MetaSVM
Uncertain
0.42
D
MutationAssessor
Uncertain
2.6
M;.;M
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.1
N;.;N
REVEL
Uncertain
0.41
Sift
Uncertain
0.0020
D;.;D
Sift4G
Uncertain
0.032
D;T;D
Polyphen
1.0
D;.;D
Vest4
0.56
MVP
0.89
MPC
1.8
ClinPred
0.060
T
GERP RS
4.9
Varity_R
0.18
gMVP
0.79

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

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

Other links and lift over

dbSNP: rs34682185; hg19: chr10-43601830; COSMIC: COSV60697066; COSMIC: COSV60697066; API