1-161306738-A-C

Position:

• chr1-161306738-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The ENST00000533357.5(MPZ):​c.418T>G​(p.Ser140Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S140T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: MPZ ENST00000533357.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.03

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in ENST00000533357.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-161306738-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPZ	NM_000530.8	c.418T>G	p.Ser140Ala	missense_variant	3/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.418T>G	p.Ser140Ala	missense_variant	3/6		NP_001302420.1
MPZ	XM_017001321.3	c.448T>G	p.Ser150Ala	missense_variant	3/6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.418T>G	p.Ser140Ala	missense_variant	3/6	1	NM_000530.8	ENSP00000432943	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.58
Sift	Benign	0.12	T
Sift4G	Benign	1.0	T
Polyphen		0.34	B
Vest4		0.61
MutPred		0.64		Loss of ubiquitination at K138 (P = 0.079);
MVP		0.93
MPC		0.85
ClinPred		0.80	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.49
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs572010627; hg19: chr1-161276528;