rs16832790

Positions:

• chr1-161306153-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000530.8(MPZ):​c.600G>A​(p.Gly200=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,614,174 control chromosomes in the GnomAD database, including 2,489 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (173 hom., cov: 32)
  • Exomes 𝑓: 0.035 (2316 hom.)
• Consequence: MPZ NM_000530.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.284

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 1-161306153-C-T is Benign according to our data. Variant chr1-161306153-C-T is described in ClinVar as [Benign]. Clinvar id is 138242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161306153-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.284 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MPZ	NM_000530.8	c.600G>A	p.Gly200=	synonymous_variant	5/6	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.600G>A	p.Gly200=	synonymous_variant	5/6		NP_001302420.1
MPZ	XM_017001321.3	c.630G>A	p.Gly210=	synonymous_variant	5/6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.600G>A	p.Gly200=	synonymous_variant	5/6	1	NM_000530.8	ENSP00000432943	P1

Frequencies

GnomAD3 genomes AF: 0.0243 AC: 3698 AN: 152196 Hom.: 173 Cov.: 32

Gnomad AFR AF: 0.00516

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0410 AC: 10321 AN: 251488 Hom.: 576 AF XY: 0.0448 AC XY: 6090 AN XY: 135920

Gnomad AFR exome AF: 0.00437

Gnomad AMR exome AF: 0.00572

Gnomad ASJ exome AF: 0.00823

Gnomad EAS exome AF: 0.169

Gnomad SAS exome AF: 0.122

Gnomad FIN exome AF: 0.00892

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0348 AC: 50801 AN: 1461862 Hom.: 2316 Cov.: 33 AF XY: 0.0373 AC XY: 27122 AN XY: 727234

Gnomad4 AFR exome AF: 0.00403

Gnomad4 AMR exome AF: 0.00595

Gnomad4 ASJ exome AF: 0.00972

Gnomad4 EAS exome AF: 0.231

Gnomad4 SAS exome AF: 0.120

Gnomad4 FIN exome AF: 0.00826

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0339

GnomAD4 genome AF: 0.0243 AC: 3695 AN: 152312 Hom.: 173 Cov.: 32 AF XY: 0.0261 AC XY: 1944 AN XY: 74478

Gnomad4 AFR AF: 0.00515

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.00668

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0214 Hom.: 42

Bravo AF: 0.0208

Asia WGS AF: 0.140 AC: 485 AN: 3478

EpiCase AF: 0.0203

EpiControl AF: 0.0216

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Roussy-Lévy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 1B;C1843153:Charcot-Marie-Tooth disease type 2J;C3888087:Charcot-Marie-Tooth disease type 2I Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 14, 2017

- -

Neuropathy, congenital hypomyelinating, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Charcot-Marie-Tooth disease dominant intermediate D Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 4E Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs16832790; hg19: chr1-161275943; COSMIC: COSV60669119;