rs144841836

chr1-161309882-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000530.8(MPZ):c.24C>T(p.Ser8=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,589,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: MPZ NM_000530.8 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.43

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-161309882-G-A is Benign according to our data. Variant chr1-161309882-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 462791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161309882-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000349 (53/152034) while in subpopulation NFE AF= 0.000662 (45/68020). AF 95% confidence interval is 0.000508. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPZ	NM_000530.8	c.24C>T	p.Ser8=	synonymous_variant	1/6	ENST00000533357.5
MPZ	NM_001315491.2	c.24C>T	p.Ser8=	synonymous_variant	1/6
MPZ	XM_017001321.3	c.54C>T	p.Ser18=	synonymous_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPZ	ENST00000533357.5	c.24C>T	p.Ser8=	synonymous_variant	1/6	1	NM_000530.8	P1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 152034 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000246 AC: 51 AN: 207406 Hom.: 0 AF XY: 0.000261 AC XY: 29 AN XY: 110978

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000699

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000222

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.000385

GnomAD4 exome AF: 0.000328 AC: 471 AN: 1437338 Hom.: 0 Cov.: 30 AF XY: 0.000341 AC XY: 243 AN XY: 712104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000101

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000369

Gnomad4 NFE exome AF: 0.000396

Gnomad4 OTH exome AF: 0.000185

GnomAD4 genome AF: 0.000349 AC: 53 AN: 152034 Hom.: 0 Cov.: 28 AF XY: 0.000364 AC XY: 27 AN XY: 74274

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000457 Hom.: 0

Bravo AF: 0.000223

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

MPZ: BP4, BP7 -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	9.1
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs144841836; hg19: chr1-161279672;