NM_000530.8:c.51G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000530.8(MPZ):c.51G>A(p.Leu17Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000029 in 1,585,776 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L17L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MPZ
NM_000530.8 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.476

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease type 1B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
neuropathy, congenital hypomyelinating, 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease dominant intermediate D
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 2I
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 2J
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Charcot-Marie-Tooth disease type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

MPZ links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 1-161309855-C-T is Benign according to our data. Variant chr1-161309855-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 511451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.476 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000184 (28/152032) while in subpopulation AFR AF = 0.000676 (28/41446). AF 95% confidence interval is 0.000479. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPZ	NM_000530.8 link	c.51G>A	p.Leu17Leu	synonymous_variant	Exon 1 of 6	ENST00000533357.5	NP_000521.2	P25189-1
MPZ	NM_001315491.2 link	c.51G>A	p.Leu17Leu	synonymous_variant	Exon 1 of 6		NP_001302420.1	P25189A0A5F9ZI26
MPZ	XM_017001321.3 link	c.81G>A	p.Leu27Leu	synonymous_variant	Exon 1 of 6		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MPZ	ENST00000533357.5 link	c.51G>A	p.Leu17Leu	synonymous_variant	Exon 1 of 6	1	NM_000530.8	ENSP00000432943.1	P25189-1
MPZ	ENST00000463290.5 link	n.51G>A		non_coding_transcript_exon_variant	Exon 1 of 7	1		ENSP00000431538.1	P25189-1
MPZ	ENST00000672602.2 link	c.51G>A	p.Leu17Leu	synonymous_variant	Exon 1 of 6			ENSP00000500814.2	A0A5F9ZI26
MPZ	ENST00000526189.3 link	c.51G>A	p.Leu17Leu	synonymous_variant	Exon 1 of 6	3		ENSP00000488104.2	A0A0J9YWT2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000678

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000343

AC:

AN:

204178

AF XY:

0.0000367

show subpopulations

Gnomad AFR exome

AF:

0.000550

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000126

AC:

AN:

1433744

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

709930

show subpopulations

African (AFR)

AF:

0.000540

AC:

AN:

33322

American (AMR)

AF:

0.00

AC:

AN:

38962

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25420

East Asian (EAS)

AF:

0.00

AC:

AN:

38916

South Asian (SAS)

AF:

0.00

AC:

AN:

81658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51442

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098844

Other (OTH)

AF:

0.00

AC:

AN:

59480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000184

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000676

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.000196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 14, 2017

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Inborn genetic diseases

Benign:1

Jul 11, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Sep 30, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease, type I

Benign:1

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.0

(source)

DANN

Benign

0.78

PhyloP100

0.48

PromoterAI

-0.048

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over