rs2075912

Positions:

chr10-43126769-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020630.7(RET):c.*15T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.814 in 1,605,984 control chromosomes in the GnomAD database, including 535,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 53076 hom., cov: 32)

Exomes 𝑓: 0.81 ( 482427 hom. )

Consequence

RET
NM_020630.7 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.43

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:

RET (HGNC:):

RET links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 10-43126769-T-C is Benign according to our data. Variant chr10-43126769-T-C is described in ClinVar as [Benign]. Clinvar id is 165056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126769-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6 linkuse as main transcript	c.3187+47T>C		intron_variant		ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.3187+47T>C		intron_variant		5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.831

AC:

126321

AN:

152062

Hom.:

53013

Cov.:

show subpopulations

Gnomad AFR

AF:

0.915

Gnomad AMI

AF:

0.920

Gnomad AMR

AF:

0.805

Gnomad ASJ

AF:

0.765

Gnomad EAS

AF:

0.499

Gnomad SAS

AF:

0.710

Gnomad FIN

AF:

0.822

Gnomad MID

AF:

0.791

Gnomad NFE

AF:

0.823

Gnomad OTH

AF:

0.822

GnomAD3 exomes

AF:

0.791

AC:

185804

AN:

235044

Hom.:

74321

AF XY:

0.788

AC XY:

100337

AN XY:

127346

show subpopulations

Gnomad AFR exome

AF:

0.917

Gnomad AMR exome

AF:

0.797

Gnomad ASJ exome

AF:

0.769

Gnomad EAS exome

AF:

0.512

Gnomad SAS exome

AF:

0.740

Gnomad FIN exome

AF:

0.811

Gnomad NFE exome

AF:

0.827

Gnomad OTH exome

AF:

0.809

GnomAD4 exome

AF:

0.812

AC:

1180522

AN:

1453804

Hom.:

482427

Cov.:

AF XY:

0.809

AC XY:

584557

AN XY:

722540

show subpopulations

Gnomad4 AFR exome

AF:

0.914

Gnomad4 AMR exome

AF:

0.796

Gnomad4 ASJ exome

AF:

0.768

Gnomad4 EAS exome

AF:

0.494

Gnomad4 SAS exome

AF:

0.743

Gnomad4 FIN exome

AF:

0.807

Gnomad4 NFE exome

AF:

0.828

Gnomad4 OTH exome

AF:

0.798

GnomAD4 genome

AF:

0.831

AC:

126448

AN:

152180

Hom.:

53076

Cov.:

AF XY:

0.828

AC XY:

61607

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.915

Gnomad4 AMR

AF:

0.805

Gnomad4 ASJ

AF:

0.765

Gnomad4 EAS

AF:

0.500

Gnomad4 SAS

AF:

0.711

Gnomad4 FIN

AF:

0.822

Gnomad4 NFE

AF:

0.823

Gnomad4 OTH

AF:

0.822

Alfa

AF:

0.826

Hom.:

53085

Bravo

AF:

0.836

Asia WGS

AF:

0.624

AC:

2171

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia type 2B

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Multiple endocrine neoplasia, type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 06, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 11, 2013

This is the major allele (http://gnomad.broadinstitute.org/variant/10-43622217-T -C). -

Pheochromocytoma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Multiple endocrine neoplasia type 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

RET-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 07, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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