rs281865132

Positions:

• chr1-161305974-G-A
• chr1-161305974-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000530.8(MPZ):​c.649C>T​(p.Pro217Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P217A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: 5.41

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000530.8
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPZ	NM_000530.8	c.649C>T	p.Pro217Ser	missense_variant	6/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.649C>T	p.Pro217Ser	missense_variant	6/6		NP_001302420.1
MPZ	XM_017001321.3	c.675+134C>T		intron_variant			XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.649C>T	p.Pro217Ser	missense_variant	6/6	1	NM_000530.8	ENSP00000432943.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

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

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D;D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.63	N;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.57	P;.
Vest4		0.29
MutPred		0.76		Gain of phosphorylation at P217 (P = 0.0153);.;
MVP		0.90
MPC		1.5
ClinPred		0.88	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.42
gMVP		0.51

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

Other links and lift over

dbSNP: rs281865132; hg19: chr1-161275764;