rs199529910
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_018972.4(GDAP1):c.965C>T(p.Thr322Met) variant causes a missense change. The variant allele was found at a frequency of 0.000177 in 1,614,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 1 hom. )
Consequence
GDAP1
NM_018972.4 missense
NM_018972.4 missense
Scores
1
10
8
Clinical Significance
Conservation
PhyloP100: 4.59
Genes affected
GDAP1 (HGNC:15968): (ganglioside induced differentiation associated protein 1) This gene encodes a member of the ganglioside-induced differentiation-associated protein family, which may play a role in a signal transduction pathway during neuronal development. Mutations in this gene have been associated with various forms of Charcot-Marie-Tooth Disease and neuropathy. Two transcript variants encoding different isoforms and a noncoding variant have been identified for this gene. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.044024974).
BP6
Variant 8-74364255-C-T is Benign according to our data. Variant chr8-74364255-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 467776.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GDAP1 | NM_018972.4 | c.965C>T | p.Thr322Met | missense_variant | 6/6 | ENST00000220822.12 | NP_061845.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GDAP1 | ENST00000220822.12 | c.965C>T | p.Thr322Met | missense_variant | 6/6 | 1 | NM_018972.4 | ENSP00000220822.7 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000298 AC: 75AN: 251414Hom.: 0 AF XY: 0.000280 AC XY: 38AN XY: 135884
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GnomAD4 exome AF: 0.000183 AC: 267AN: 1461866Hom.: 1 Cov.: 32 AF XY: 0.000180 AC XY: 131AN XY: 727228
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GnomAD4 genome AF: 0.000125 AC: 19AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74326
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 25, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 11, 2021 | This variant is associated with the following publications: (PMID: 25614874) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 21, 2023 | BS1 - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Charcot-Marie-Tooth disease recessive intermediate A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 27, 2022 | 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. - |
Charcot-Marie-Tooth disease type 4A Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 26, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at