chr1-161306866-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000530.8(MPZ):​c.290A>T​(p.Glu97Val) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 29)

Consequence

MPZ
NM_000530.8 missense

Scores

3
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 5.57
Variant links:
Genes affected
MPZ (HGNC:7225): (myelin protein zero) This gene is specifically expressed in Schwann cells of the peripheral nervous system and encodes a type I transmembrane glycoprotein that is a major structural protein of the peripheral myelin sheath. The encoded protein contains a large hydrophobic extracellular domain and a smaller basic intracellular domain, which are essential for the formation and stabilization of the multilamellar structure of the compact myelin. Mutations in this gene are associated with autosomal dominant form of Charcot-Marie-Tooth disease type 1 (CMT1B) and other polyneuropathies, such as Dejerine-Sottas syndrome (DSS) and congenital hypomyelinating neuropathy (CHN). A recent study showed that two isoforms are produced from the same mRNA by use of alternative in-frame translation termination codons via a stop codon readthrough mechanism. [provided by RefSeq, Oct 2015]

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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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000530.8
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MPZNM_000530.8 linkuse as main transcriptc.290A>T p.Glu97Val missense_variant 3/6 ENST00000533357.5
MPZNM_001315491.2 linkuse as main transcriptc.290A>T p.Glu97Val missense_variant 3/6
MPZXM_017001321.3 linkuse as main transcriptc.320A>T p.Glu107Val missense_variant 3/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MPZENST00000533357.5 linkuse as main transcriptc.290A>T p.Glu97Val missense_variant 3/61 NM_000530.8 P1P25189-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
29

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease type 2J Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 24, 2004- -
Charcot-Marie-Tooth disease, type I Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 06, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 15326256). ClinVar contains an entry for this variant (Variation ID: 14195). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with valine at codon 97 of the MPZ protein (p.Glu97Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.63
D
Eigen
Benign
0.064
Eigen_PC
Benign
0.20
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.77
T
M_CAP
Benign
0.052
D
MetaRNN
Pathogenic
0.82
D
MetaSVM
Benign
-0.83
T
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.7
D
REVEL
Uncertain
0.49
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.041
D
Polyphen
0.25
B
Vest4
0.86
MutPred
0.72
Gain of sheet (P = 0.0477);
MVP
0.96
MPC
0.68
ClinPred
0.98
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.87
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913606; hg19: chr1-161276656; API