chr10-43100520-A-G

Position:

chr10-43100520-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_020975.6(RET):c.135A>G(p.Ala45=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 1,613,574 control chromosomes in the GnomAD database, including 451,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.79 ( 47935 hom., cov: 32)

Exomes 𝑓: 0.74 ( 403068 hom. )

Consequence

RET
NM_020975.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.19

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 10-43100520-A-G is Benign according to our data. Variant chr10-43100520-A-G is described in ClinVar as [Benign]. Clinvar id is 167589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100520-A-G is described in Lovd as [Benign]. Variant chr10-43100520-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.19 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.941 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.135A>G	p.Ala45=	synonymous_variant	2/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.135A>G	p.Ala45=	synonymous_variant	2/20	5	NM_020975.6	ENSP00000347942	P4	P07949-1

Frequencies

GnomAD3 genomes

AF:

0.785

AC:

119303

AN:

151974

Hom.:

47871

Cov.:

show subpopulations

Gnomad AFR

AF:

0.949

Gnomad AMI

AF:

0.834

Gnomad AMR

AF:

0.756

Gnomad ASJ

AF:

0.701

Gnomad EAS

AF:

0.548

Gnomad SAS

AF:

0.707

Gnomad FIN

AF:

0.638

Gnomad MID

AF:

0.715

Gnomad NFE

AF:

0.742

Gnomad OTH

AF:

0.773

GnomAD3 exomes

AF:

0.731

AC:

182618

AN:

249766

Hom.:

67582

AF XY:

0.728

AC XY:

98390

AN XY:

135202

show subpopulations

Gnomad AFR exome

AF:

0.953

Gnomad AMR exome

AF:

0.759

Gnomad ASJ exome

AF:

0.704

Gnomad EAS exome

AF:

0.551

Gnomad SAS exome

AF:

0.729

Gnomad FIN exome

AF:

0.640

Gnomad NFE exome

AF:

0.740

Gnomad OTH exome

AF:

0.741

GnomAD4 exome

AF:

0.741

AC:

1082809

AN:

1461482

Hom.:

403068

Cov.:

AF XY:

0.740

AC XY:

537731

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.953

Gnomad4 AMR exome

AF:

0.758

Gnomad4 ASJ exome

AF:

0.706

Gnomad4 EAS exome

AF:

0.566

Gnomad4 SAS exome

AF:

0.732

Gnomad4 FIN exome

AF:

0.647

Gnomad4 NFE exome

AF:

0.746

Gnomad4 OTH exome

AF:

0.740

GnomAD4 genome

AF:

0.785

AC:

119435

AN:

152092

Hom.:

47935

Cov.:

AF XY:

0.778

AC XY:

57826

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.949

Gnomad4 AMR

AF:

0.756

Gnomad4 ASJ

AF:

0.701

Gnomad4 EAS

AF:

0.549

Gnomad4 SAS

AF:

0.708

Gnomad4 FIN

AF:

0.638

Gnomad4 NFE

AF:

0.742

Gnomad4 OTH

AF:

0.772

Alfa

AF:

0.759

Hom.:

23229

Bravo

AF:

0.803

Asia WGS

AF:

0.654

AC:

2275

AN:

3478

EpiCase

AF:

0.739

EpiControl

AF:

0.745

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 12, 2018	This "variant" is a RefSeq error. G at this position is the major allele with an allele frequency of 73.6% in gnomAD (http://gnomad.broadinstitute.org/variant/1 0-43595968-A-G). -

Multiple endocrine neoplasia, type 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 06, 2019	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Multiple endocrine neoplasia type 2B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.024

DANN

Benign

0.31

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

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