chr10-43118395-G-T

Position:

chr10-43118395-G-T

Variant summary

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

The NM_020975.6(RET):c.2307G>T(p.Leu769=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 1,613,240 control chromosomes in the GnomAD database, including 467,321 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. L769L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.78 ( 47440 hom., cov: 33)

Exomes 𝑓: 0.76 ( 419881 hom. )

Consequence

RET
NM_020975.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.28

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=-0.48).

BP6

Variant 10-43118395-G-T is Benign according to our data. Variant chr10-43118395-G-T is described in ClinVar as [Benign]. Clinvar id is 167590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43118395-G-T is described in Lovd as [Benign]. Variant chr10-43118395-G-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=1.28 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6 linkuse as main transcript	c.2307G>T	p.Leu769=	synonymous_variant	13/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.2307G>T	p.Leu769=	synonymous_variant	13/20	5	NM_020975.6	P4	P07949-1

Frequencies

GnomAD3 genomes

AF:

0.785

AC:

119297

AN:

152042

Hom.:

47391

Cov.:

show subpopulations

Gnomad AFR

AF:

0.883

Gnomad AMI

AF:

0.822

Gnomad AMR

AF:

0.766

Gnomad ASJ

AF:

0.711

Gnomad EAS

AF:

0.495

Gnomad SAS

AF:

0.620

Gnomad FIN

AF:

0.782

Gnomad MID

AF:

0.728

Gnomad NFE

AF:

0.767

Gnomad OTH

AF:

0.760

GnomAD3 exomes

AF:

0.739

AC:

185430

AN:

250848

Hom.:

69586

AF XY:

0.732

AC XY:

99313

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.885

Gnomad AMR exome

AF:

0.771

Gnomad ASJ exome

AF:

0.714

Gnomad EAS exome

AF:

0.506

Gnomad SAS exome

AF:

0.643

Gnomad FIN exome

AF:

0.767

Gnomad NFE exome

AF:

0.769

Gnomad OTH exome

AF:

0.753

GnomAD4 exome

AF:

0.755

AC:

1103576

AN:

1461080

Hom.:

419881

Cov.:

AF XY:

0.751

AC XY:

545784

AN XY:

726868

show subpopulations

Gnomad4 AFR exome

AF:

0.883

Gnomad4 AMR exome

AF:

0.769

Gnomad4 ASJ exome

AF:

0.714

Gnomad4 EAS exome

AF:

0.484

Gnomad4 SAS exome

AF:

0.646

Gnomad4 FIN exome

AF:

0.761

Gnomad4 NFE exome

AF:

0.771

Gnomad4 OTH exome

AF:

0.745

GnomAD4 genome

AF:

0.785

AC:

119408

AN:

152160

Hom.:

47440

Cov.:

AF XY:

0.782

AC XY:

58150

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.883

Gnomad4 AMR

AF:

0.766

Gnomad4 ASJ

AF:

0.711

Gnomad4 EAS

AF:

0.495

Gnomad4 SAS

AF:

0.621

Gnomad4 FIN

AF:

0.782

Gnomad4 NFE

AF:

0.767

Gnomad4 OTH

AF:

0.760

Alfa

AF:

0.773

Hom.:

29403

Bravo

AF:

0.792

Asia WGS

AF:

0.591

AC:

2057

AN:

3478

EpiCase

AF:

0.759

EpiControl

AF:

0.766

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	Oct 11, 2013	Leu769Leu in exon 13 of RET: This variant is not expected to have clinical signi ficance because it has been identified in 23% (2018/8600) of European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs1800861). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2016	- -

Multiple endocrine neoplasia, type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

4.9

DANN

Benign

0.73

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