chr8-74360225-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_018972.4(GDAP1):c.399G>A(p.Met133Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000345 in 1,612,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00036 ( 0 hom. )
Consequence
GDAP1
NM_018972.4 missense
NM_018972.4 missense
Scores
4
10
5
Clinical Significance
Conservation
PhyloP100: 7.70
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 Uncertain_significance. Variant got 5 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_018972.4
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 8-74360225-G-A is Pathogenic according to our data. Variant chr8-74360225-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245607.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=3, Likely_pathogenic=1}. Variant chr8-74360225-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GDAP1 | NM_018972.4 | c.399G>A | p.Met133Ile | missense_variant | 3/6 | ENST00000220822.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GDAP1 | ENST00000220822.12 | c.399G>A | p.Met133Ile | missense_variant | 3/6 | 1 | NM_018972.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000158 AC: 24AN: 152054Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000107 AC: 27AN: 251478Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135912
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14702039, 26392352, 32376792) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 02, 2021 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2023 | The c.399G>A (p.M133I) alteration is located in exon 3 (coding exon 3) of the GDAP1 gene. This alteration results from a G to A substitution at nucleotide position 399, causing the methionine (M) at amino acid position 133 to be replaced by an isoleucine (I)._x000D_ _x000D_ Based on the available evidence, the c.399G>A (p.M133I) alteration alteration is classified as likely pathogenic for autosomal recessive GDAP1-related Charcot-Marie-Tooth disease; however, it is unlikely to be causative of autosomal dominant GDAP1-related Charcot-Marie-Tooth disease, type 2. Based on data from gnomAD, the A allele has an overall frequency of 0.011% (31/282872) total alleles studied. The highest observed frequency was 0.024% (31/129184) of European (non-Finnish) alleles. This alteration was detected in conjunction with another alteration in GDAP1, in multiple individuals with features consistent with GDAP1-related Charcot-Marie-Tooth disease (external communication). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Charcot-Marie-Tooth disease type 4A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 133 of the GDAP1 protein (p.Met133Ile). This variant is present in population databases (rs139808557, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of autosomal recessive Charcot-Marie-Tooth disease (PMID: 26392352, 32376792; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 245607). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 04, 2023 | Variant summary: GDAP1 c.399G>A (p.Met133Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 251478 control chromosomes. c.399G>A has been reported in the literature in at least one individual affected with Charcot-Marie Disease type 4A, without a reported second variant (e.g. Antoniadi_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Charcot-Marie Disease Type 4A. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26392352). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=2) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Uncertain
D;D
Polyphen
B;.
Vest4
MutPred
Gain of loop (P = 0.069);.;
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at