NM_020975.6:c.3142C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS1

The NM_020975.6(RET):c.3142C>T(p.Leu1048Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000328 in 1,614,096 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1048V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.96

Publications

3 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1164158).

BP6

Variant 10-43126677-C-T is Benign according to our data. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43126677-C-T is described in CliVar as Likely_benign. Clinvar id is 241357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000342 (50/1461840) while in subpopulation AMR AF = 0.00112 (50/44724). AF 95% confidence interval is 0.00087. There are 0 homozygotes in GnomAdExome4. There are 27 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.3142C>T	p.Leu1048Phe	missense_variant	Exon 19 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.3142C>T	p.Leu1048Phe	missense_variant	Exon 19 of 20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000175

AC:

AN:

251468

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00112

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:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.0000197

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:2

Dec 29, 2018

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. -

Feb 19, 2022

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Multiple endocrine neoplasia, type 2

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RET-related disorder

Benign:1

May 11, 2024

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

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.054

MetaRNN

Benign

0.12

T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Benign

0.69

N;N

PhyloP100

5.0

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.37

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.99

D;D

Vest4

0.75

MutPred

0.30

Loss of disorder (P = 0.0819);Loss of disorder (P = 0.0819);

MVP

0.53

MPC

0.51

ClinPred

0.17

GERP RS

5.1

Varity_R

0.40

gMVP

0.46

Mutation Taster

=22/78

disease causing

(source)

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