10-43120185-C-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BA1

The NM_020975.6(RET):c.2712C>G(p.Ser904=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,612,614 control chromosomes in the GnomAD database, including 29,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S904S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2538 hom., cov: 33)
  • Exomes 𝑓: 0.19 (27229 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.752

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 10-43120185-C-G is Benign according to our data. Variant chr10-43120185-C-G is described in ClinVar as [Benign]. Clinvar id is 24964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43120185-C-G 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	UniProt
RET	NM_020975.6	c.2712C>G	p.Ser904=	synonymous_variant	15/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.2712C>G	p.Ser904=	synonymous_variant	15/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26367 AN: 152066 Hom.: 2539 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.183

GnomAD3 exomes AF: 0.211 AC: 52714 AN: 249546 Hom.: 6289 AF XY: 0.209 AC XY: 28316 AN XY: 135222

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.353

Gnomad ASJ exome AF: 0.194

Gnomad EAS exome AF: 0.115

Gnomad SAS exome AF: 0.256

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.186

Gnomad OTH exome AF: 0.222

GnomAD4 exome AF: 0.187 AC: 273006 AN: 1460432 Hom.: 27229 Cov.: 36 AF XY: 0.189 AC XY: 137082 AN XY: 726482

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.339

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.0944

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.213

Gnomad4 NFE exome AF: 0.179

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.173 AC: 26373 AN: 152182 Hom.: 2538 Cov.: 33 AF XY: 0.177 AC XY: 13143 AN XY: 74404

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.248

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.184

Gnomad4 OTH AF: 0.180

Alfa AF: 0.186 Hom.: 879

Bravo AF: 0.174

Asia WGS AF: 0.171 AC: 595 AN: 3478

EpiCase AF: 0.190

EpiControl AF: 0.196

ClinVar

Significance: Benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 11, 2013	Ser904Ser in exon 15 of RET: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence, and has been identified in 19% (1604/8598) of Euro pean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1800863). -

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	Mar 28, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2017	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hirschsprung disease, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Renal hypodysplasia/aplasia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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
BayesDel_noAF	Benign	-0.30
Cadd	Benign	17
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.52		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1800863; hg19: chr10-43615633; COSMIC: COSV60687135;