Variant 1-161307418-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000530.8(MPZ):c.74C>T(p.Ser25Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MPZ
NM_000530.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.08

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]

MPZ links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a signal_peptide (size 28) in uniprot entity MYP0_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000530.8

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12542501).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MPZ	NM_000530.8 linkuse as main transcript	c.74C>T	p.Ser25Phe	missense_variant	2/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2 linkuse as main transcript	c.74C>T	p.Ser25Phe	missense_variant	2/6		NP_001302420.1
MPZ	XM_017001321.3 linkuse as main transcript	c.104C>T	p.Ser35Phe	missense_variant	2/6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5 linkuse as main transcript	c.74C>T	p.Ser25Phe	missense_variant	2/6	1	NM_000530.8	ENSP00000432943	P1	P25189-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.48

M_CAP

Benign

0.078

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.31

Sift

Uncertain

0.0030

Sift4G

Benign

0.16

Polyphen

0.0050

Vest4

0.22

MutPred

0.53

Loss of glycosylation at S20 (P = 0.1443);

MVP

0.31

MPC

0.60

ClinPred

0.14

GERP RS

2.2

Varity_R

0.096

gMVP

0.61

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over