rs34307129

Variant names:

• chr1-161305939-G-A
• rs34307129
• NM_000530.8:c.684C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000530.8(MPZ):​c.684C>T​(p.Ser228Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.0244 in 1,613,780 control chromosomes in the GnomAD database, including 576 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (36 hom., cov: 31)
  • Exomes 𝑓: 0.025 (540 hom.)
• Consequence: MPZ NM_000530.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.09
• Publications: 4 publications found

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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), 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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-161305939-G-A is Benign according to our data. Variant chr1-161305939-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.019 (2886/152092) while in subpopulation NFE AF = 0.0299 (2035/67978). AF 95% confidence interval is 0.0289. There are 36 homozygotes in GnomAd4. There are 1438 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2886 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000530.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPZ	NM_000530.8	MANE Select	c.684C>T	p.Ser228Ser	synonymous	Exon 6 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.684C>T	p.Ser228Ser	synonymous	Exon 6 of 6	NP_001302420.1	A0A5F9ZI26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPZ	ENST00000533357.5	TSL:1 MANE Select	c.684C>T	p.Ser228Ser	synonymous	Exon 6 of 6	ENSP00000432943.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.684C>T		non_coding_transcript_exon	Exon 6 of 7	ENSP00000431538.1	P25189-1
	MPZ	ENST00000672602.2		c.684C>T	p.Ser228Ser	synonymous	Exon 6 of 6	ENSP00000500814.2	A0A5F9ZI26

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2887 AN: 151974 Hom.: 37 Cov.: 31

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0220

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0300

Gnomad OTH AF: 0.0259

GnomAD2 exomes AF: 0.0197 AC: 4922 AN: 250156 AF XY: 0.0197

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.0313

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0250 AC: 36542 AN: 1461688 Hom.: 540 Cov.: 33 AF XY: 0.0248 AC XY: 18030 AN XY: 727162

African (AFR) AF: 0.00418 AC: 140 AN: 33478

American (AMR) AF: 0.0147 AC: 659 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00256 AC: 221 AN: 86256

European-Finnish (FIN) AF: 0.0261 AC: 1393 AN: 53418

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5768

European-Non Finnish (NFE) AF: 0.0294 AC: 32741 AN: 1111834

Other (OTH) AF: 0.0202 AC: 1219 AN: 60388

GnomAD4 genome AF: 0.0190 AC: 2886 AN: 152092 Hom.: 36 Cov.: 31 AF XY: 0.0193 AC XY: 1438 AN XY: 74346

African (AFR) AF: 0.00424 AC: 176 AN: 41488

American (AMR) AF: 0.0220 AC: 336 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.0240 AC: 254 AN: 10590

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0299 AC: 2035 AN: 67978

Other (OTH) AF: 0.0256 AC: 54 AN: 2108

Alfa AF: 0.0267 Hom.: 132

Bravo AF: 0.0175

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0295

EpiControl AF: 0.0296

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease dominant intermediate D (1)
-	-	1	Charcot-Marie-Tooth disease type 1B (1)
-	-	1	Charcot-Marie-Tooth disease type 4E (1)
-	-	1	Charcot-Marie-Tooth disease, type I (1)
-	-	1	Neuropathy, congenital hypomyelinating, 2 (1)
-	-	1	Roussy-Lévy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Uncertain	1.0
PhyloP100		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34307129; hg19: chr1-161275729;