rs2435357

Positions:

• chr10-43086608-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020975.6(RET):​c.73+9277T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.789 in 152,304 control chromosomes in the GnomAD database, including 48,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (★★).

• Frequency: Genomes: 𝑓 0.79 (48464 hom., cov: 34)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Benign; risk factor criteria provided, multiple submitters, no conflicts B:3 O:3
• Conservation: PhyloP100: -1.19

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-43086608-T-C is Benign according to our data. Variant chr10-43086608-T-C is described in ClinVar as [Benign, risk_factor]. Clinvar id is 13952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.73+9277T>C		intron_variant		ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.73+9277T>C		intron_variant		5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes AF: 0.789 AC: 120018 AN: 152186 Hom.: 48396 Cov.: 34

Gnomad AFR AF: 0.952

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.748

Gnomad OTH AF: 0.776

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.789 AC: 120154 AN: 152304 Hom.: 48464 Cov.: 34 AF XY: 0.781 AC XY: 58179 AN XY: 74468

Gnomad4 AFR AF: 0.952

Gnomad4 AMR AF: 0.763

Gnomad4 ASJ AF: 0.699

Gnomad4 EAS AF: 0.544

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.748

Gnomad4 OTH AF: 0.775

Alfa AF: 0.764 Hom.: 13672

Bravo AF: 0.808

Asia WGS AF: 0.652 AC: 2268 AN: 3478

ClinVar

Significance: Benign; risk factor

Submissions summary: Benign:3 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hirschsprung disease, susceptibility to, 1 Other:2

risk factor, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 19, 2020	A heterozygous variant c.73+9277T>C in intron 1 of the RET gene was detected. Presence of this allele has been identified to increase risk of Hirschprung disease by 5.7X compared to people who don't carry the variant (Virtanen et al. EJHG 2019). The allele frequency for the variant is 0.774 as given in gnomAD genomes. In summary, the variant meets our criteria to be classified as a risk factor for Hirschprung disease. -
risk factor, no assertion criteria provided	literature only	OMIM	Jul 09, 2010	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 06, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Multiple endocrine neoplasia, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Aganglionic megacolon Other:1

risk factor, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

Nov 20, 2017

This variant was identified in a patient with Hirschsprung disease and a positive familial history. The patient harbours also a variant in the SEMA3D gene, which is a VUS for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.47
DANN	Benign	0.60

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

Other links and lift over

dbSNP: rs2435357; hg19: chr10-43582056;