rs372051998

Variant summary

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

The NM_000530.8(MPZ):ā€‹c.542A>Gā€‹(p.Tyr181Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 152,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Synonymous variant affecting the same amino acid position (i.e. Y181Y) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)

Consequence

MPZ
NM_000530.8 missense

Scores

4
10
5

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.800
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a chain Myelin protein P0 (size 218) in uniprot entity MYP0_HUMAN there are 268 pathogenic changes around while only 9 benign (97%) in NM_000530.8
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MPZNM_000530.8 linkuse as main transcriptc.542A>G p.Tyr181Cys missense_variant 4/6 ENST00000533357.5 NP_000521.2 P25189-1
MPZNM_001315491.2 linkuse as main transcriptc.542A>G p.Tyr181Cys missense_variant 4/6 NP_001302420.1 P25189A0A5F9ZI26
MPZXM_017001321.3 linkuse as main transcriptc.572A>G p.Tyr191Cys missense_variant 4/6 XP_016856810.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MPZENST00000533357.5 linkuse as main transcriptc.542A>G p.Tyr181Cys missense_variant 4/61 NM_000530.8 ENSP00000432943.1 P25189-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152014
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152014
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74240
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 23, 2023Reported as a paternally inherited variant in a family with neuropathy in published literature (Kushlaf et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20461396, 26310628, Kushlaf2019[casereport]) -
Charcot-Marie-Tooth disease, type I Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 08, 2018This sequence change replaces tyrosine with cysteine at codon 181 of the MPZ protein (p.Tyr181Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MPZ-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T
Eigen
Uncertain
0.25
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.83
T
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.81
D
MetaSVM
Uncertain
0.051
D
MutationAssessor
Benign
0.90
L
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.2
N
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0080
D
Sift4G
Uncertain
0.048
D
Polyphen
1.0
D
Vest4
0.73
MVP
0.90
MPC
1.6
ClinPred
0.95
D
GERP RS
3.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.14
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs372051998; hg19: chr1-161276161; API