rs121913588

Positions:

• chr1-161306747-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000530.8(MPZ):​c.409G>A​(p.Gly137Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.54

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a strand (size 14) in uniprot entity MYP0_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) 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 chr1-161306746-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 1-161306747-C-T is Pathogenic according to our data. Variant chr1-161306747-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161306747-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPZ	NM_000530.8	c.409G>A	p.Gly137Ser	missense_variant	3/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.409G>A	p.Gly137Ser	missense_variant	3/6		NP_001302420.1
MPZ	XM_017001321.3	c.439G>A	p.Gly147Ser	missense_variant	3/6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.409G>A	p.Gly137Ser	missense_variant	3/6	1	NM_000530.8	ENSP00000432943	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1996

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 06, 2017

- -

Charcot-Marie-Tooth disease, type I Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 21, 2021

This sequence change replaces glycine with serine at codon 137 of the MPZ protein (p.Gly137Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 8664899, 11545686, 26310628, Invitae). ClinVar contains an entry for this variant (Variation ID: 14173). Experimental studies have shown that this variant does not substantially affect MPZ protein function (PMID: 29687021). This variant disrupts the p.Gly137 amino acid residue in MPZ. Other variant(s) that disrupt this residue have been observed in individuals with MPZ-related conditions (PMID: 21326314, 24053775), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.79
Sift	Benign	0.54	T
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.72
MutPred		0.71		Gain of disorder (P = 0.0501);
MVP		0.94
MPC		1.5
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.50		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs121913588; hg19: chr1-161276537;