1-161307389-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_000530.8(MPZ):​c.103G>C​(p.Asp35His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D35E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

MPZ
NM_000530.8 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.36
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 hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000530.8
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-161307389-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 462790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.3634635).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MPZNM_000530.8 linkuse as main transcriptc.103G>C p.Asp35His missense_variant 2/6 ENST00000533357.5
MPZNM_001315491.2 linkuse as main transcriptc.103G>C p.Asp35His missense_variant 2/6
MPZXM_017001321.3 linkuse as main transcriptc.133G>C p.Asp45His missense_variant 2/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MPZENST00000533357.5 linkuse as main transcriptc.103G>C p.Asp35His missense_variant 2/61 NM_000530.8 P1P25189-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Charcot-Marie-Tooth disease dominant intermediate D Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, Cologne UniversityMar 27, 2020ACMG-Criteria PM2, PM5, PP3. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.28
T
Eigen
Benign
0.17
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.84
T
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.36
T
MetaSVM
Uncertain
0.29
D
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-2.3
N
REVEL
Uncertain
0.44
Sift
Benign
0.18
T
Sift4G
Benign
0.14
T
Polyphen
0.56
P
Vest4
0.27
MutPred
0.59
Gain of disorder (P = 0.0886);
MVP
0.82
MPC
0.65
ClinPred
0.83
D
GERP RS
5.3
Varity_R
0.66
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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: rs121913596; hg19: chr1-161277179; API