1-161305779-G-A

Variant names:

• chr1-161305779-G-A
• NM_000530.8:c.*97C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001315491.2(MPZ):​c.844C>T​(p.Gln282*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MPZ NM_001315491.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.760
• Publications: 0 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, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.101 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001315491.2. 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.*97C>T		3_prime_UTR	Exon 6 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.844C>T	p.Gln282*	stop_gained	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.*97C>T		3_prime_UTR	Exon 6 of 6	ENSP00000432943.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.*97C>T		non_coding_transcript_exon	Exon 6 of 7	ENSP00000431538.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.*97C>T		3_prime_UTR	Exon 6 of 7	ENSP00000431538.1	P25189-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 757646 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 390508

African (AFR) AF: 0.00 AC: 0 AN: 19228

American (AMR) AF: 0.00 AC: 0 AN: 27878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16530

East Asian (EAS) AF: 0.00 AC: 0 AN: 34808

South Asian (SAS) AF: 0.00 AC: 0 AN: 58314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44696

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2606

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 517212

Other (OTH) AF: 0.00 AC: 0 AN: 36374

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.92
PhyloP100		0.76
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-161275569;