chr10-43114547-G-A

Position:

• chr10-43114547-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_020975.6(RET):​c.1947G>A​(p.Ser649=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -3.14

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-43114547-G-A is Pathogenic according to our data. Variant chr10-43114547-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 24929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.1947G>A	p.Ser649=	synonymous_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.1947G>A	p.Ser649=	synonymous_variant	11/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458686 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hirschsprung disease, susceptibility to, 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Feb 01, 2022	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Mar 10, 2021	ACMG codes:PS4, PS3, PM2, PP5 -

Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1275808:Congenital central hypoventilation;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

This sequence change affects codon 649 of the RET mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the RET protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Hirschsprung disease (PMID: 10618407, 21712996). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24929). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2024

RNA studies demonstrate a damaging effect: a partial splice defect leading to an in-frame loss of 23 residues and a predicted hypomorphic allele (PMID: 10618407); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16448984, 10090908, 11955539, 21712996, 8896569, 10618407, 36474027, 14633923) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2022

The c.1947G>A variant (also known as p.S649S), located in coding exon 11 of the RET gene, results from a G to A substitution at nucleotide position 1947. This nucleotide substitution does not change the serine at codon 649. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site. This alteration has been reported in multiple families affected with Hirschprung disease in the literature (Salomon R et al. Nat Genet, 1996 Nov;14:345-7; Auricchio A et al. Am J Hum Genet, 1999 Apr;64:1216-21; Bolk S et al. Proc Natl Acad Sci U S A, 2000 Jan;97:268-73). Bolk et al. performed RT-PCR analysis on RNA from a lymphoblastoid line demonstrating that the alteration creates a novel splice acceptor site within RET and partial novel splice site usage results in the deletion of first 23 amino acids of exon 11. Authors concluded that based on partial usage of the novel splice acceptor site, the S649S mutation is a hypomorphic allele (Bolk S et al. Proc Natl Acad Sci U S A, 2000 Jan;97:268-73). Based on the supporting evidence, this alteration is likely pathogenic for Hirschsprung disease; however, the association of this alteration with MEN2 is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs377767412; hg19: chr10-43609995;