rs104894627
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000304.4(PMP22):c.110A>T(p.Asp37Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D37H) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 31)
Consequence
PMP22
NM_000304.4 missense
NM_000304.4 missense
Scores
8
6
2
Clinical Significance
Conservation
PhyloP100: 4.18
Genes affected
PMP22 (HGNC:9118): (peripheral myelin protein 22) This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM1
?
In a chain Peripheral myelin protein 22 (size 159) in uniprot entity PMP22_HUMAN there are 98 pathogenic changes around while only 10 benign (91%) in NM_000304.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
?
Variant 17-15259162-T-A is Pathogenic according to our data. Variant chr17-15259162-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 8442.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-15259162-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMP22 | NM_000304.4 | c.110A>T | p.Asp37Val | missense_variant | 3/5 | ENST00000312280.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMP22 | ENST00000312280.9 | c.110A>T | p.Asp37Val | missense_variant | 3/5 | 1 | NM_000304.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease, type 1a, with focally folded myelin sheaths Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 11, 1999 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Pathogenic
D;D;D;D;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;.;.;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;.;.;.;.
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;D;.;D;.;D
Polyphen
D;D;D;.;.;.;.
Vest4
MutPred
Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);
MVP
MPC
1.6
ClinPred
D
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