chr10-43111329-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBP7

The NM_020975.6(RET):c.1386G>A(p.Ser462Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,614,002 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 benign (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

RET
NM_020975.6 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.94

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

familial medullary thyroid carcinoma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
multiple endocrine neoplasia type 2A
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
multiple endocrine neoplasia type 2B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
pheochromocytoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Hirschsprung disease, susceptibility to, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Haddad syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hirschsprung disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
bilateral renal agenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis
Inheritance: AR Classification: LIMITED Submitted by: G2P

RET links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 10-43111329-G-A is Benign according to our data. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111329-G-A is described in CliVar as Likely_benign. Clinvar id is 136099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.94 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.1386G>A	p.Ser462Ser	synonymous_variant	Exon 7 of 20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.1386G>A	p.Ser462Ser	synonymous_variant	Exon 7 of 20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251454

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

1112010

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

Oct 20, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Oct 14, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not specified

Benign:1

Jun 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Multiple endocrine neoplasia, type 2

Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RET: BP4, BP7 -

RET-related disorder

Benign:1

May 29, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

-0.75

CADD

Benign

0.12

(source)

DANN

Benign

0.44

PhyloP100

-1.9

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over