NM_020975.6:c.3142C>T

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

11
8

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

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
RETNM_020975.6 linkc.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
RETENST00000355710.8 linkc.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:
3
AN:
152138
Hom.:
0
Cov.:
32
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:
44
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:
50
AN:
1461840
Hom.:
0
Cov.:
31
AF XY:
0.0000371
AC XY:
27
AN XY:
727210
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00112
AC:
50
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53390
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111990
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
4
8
11
15
19
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
3
AN:
152256
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74440
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41532
American (AMR)
AF:
0.000131
AC:
2
AN:
15300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5172
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4812
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000756
ExAC
AF:
0.0000988
AC:
12

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
T
BayesDel_noAF
Benign
-0.12
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;.
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.12
T;T
MetaSVM
Uncertain
0.14
D
MutationAssessor
Benign
0.69
N;N
PhyloP100
5.0
PrimateAI
Uncertain
0.63
T
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
T
GERP RS
5.1
Varity_R
0.40
gMVP
0.46
Mutation Taster
=22/78
disease causing

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

Other links and lift over

dbSNP: rs774347808; hg19: chr10-43622125; API