rs1553260014

Variant names:

• chr1-161309838-C-T
• rs1553260014
• NM_000530.8:c.67+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000530.8(MPZ):​c.67+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MPZ NM_000530.8 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.58
• 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-161309838-C-T is Pathogenic according to our data. Variant chr1-161309838-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 447733.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPZ	NM_000530.8	c.67+1G>A		splice_donor_variant, intron_variant	Intron 1 of 5	ENST00000533357.5	NP_000521.2
MPZ	NM_001315491.2	c.67+1G>A		splice_donor_variant, intron_variant	Intron 1 of 5		NP_001302420.1
MPZ	XM_017001321.3	c.97+1G>A		splice_donor_variant, intron_variant	Intron 1 of 5		XP_016856810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPZ	ENST00000533357.5	c.67+1G>A		splice_donor_variant, intron_variant	Intron 1 of 5	1	NM_000530.8	ENSP00000432943.1
MPZ	ENST00000463290.5	n.67+1G>A		splice_donor_variant, intron_variant	Intron 1 of 6	1		ENSP00000431538.1
MPZ	ENST00000672602.2	c.67+1G>A		splice_donor_variant, intron_variant	Intron 1 of 5			ENSP00000500814.2
MPZ	ENST00000526189.3	c.67+1G>A		splice_donor_variant, intron_variant	Intron 1 of 5	3		ENSP00000488104.2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426864 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 705888

African (AFR) AF: 0.00 AC: 0 AN: 33268

American (AMR) AF: 0.00 AC: 0 AN: 37758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25342

East Asian (EAS) AF: 0.00 AC: 0 AN: 38750

South Asian (SAS) AF: 0.00 AC: 0 AN: 81144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51012

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094640

Other (OTH) AF: 0.00 AC: 0 AN: 59244

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 28, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.80	D
PhyloP100		3.6
GERP RS		4.7
PromoterAI		-0.22	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: 1

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

Other links and lift over

dbSNP: rs1553260014; hg19: chr1-161279628;