1-161305681-C-A

Variant names:

• chr1-161305681-C-A
• rs150182811
• NM_000530.8:c.*195G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000530.8(MPZ):​c.*195G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00933 in 590,924 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0082 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0097 (32 hom.)
• Consequence: MPZ NM_000530.8 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.36
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-161305681-C-A is Benign according to our data. Variant chr1-161305681-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 293310.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0082 (1243/151548) while in subpopulation NFE AF = 0.0133 (904/67830). AF 95% confidence interval is 0.0126. There are 6 homozygotes in GnomAd4. There are 594 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1243 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.*195G>T		3_prime_UTR	Exon 6 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.*3G>T		3_prime_UTR	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.*195G>T		3_prime_UTR	Exon 6 of 6	ENSP00000432943.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.*195G>T		non_coding_transcript_exon	Exon 6 of 7	ENSP00000431538.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.*195G>T		3_prime_UTR	Exon 6 of 7	ENSP00000431538.1	P25189-1

Frequencies

GnomAD3 genomes AF: 0.00821 AC: 1243 AN: 151428 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00204

Gnomad AMI AF: 0.0341

Gnomad AMR AF: 0.00624

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00147

Gnomad FIN AF: 0.00989

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00627

GnomAD4 exome AF: 0.00971 AC: 4268 AN: 439376 Hom.: 32 Cov.: 3 AF XY: 0.00911 AC XY: 2101 AN XY: 230662

African (AFR) AF: 0.00238 AC: 29 AN: 12208

American (AMR) AF: 0.00387 AC: 68 AN: 17564

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 14 AN: 13518

East Asian (EAS) AF: 0.0000982 AC: 3 AN: 30556

South Asian (SAS) AF: 0.00186 AC: 80 AN: 43112

European-Finnish (FIN) AF: 0.0165 AC: 498 AN: 30164

Middle Eastern (MID) AF: 0.00155 AC: 3 AN: 1934

European-Non Finnish (NFE) AF: 0.0126 AC: 3327 AN: 264744

Other (OTH) AF: 0.00962 AC: 246 AN: 25576

GnomAD4 genome AF: 0.00820 AC: 1243 AN: 151548 Hom.: 6 Cov.: 31 AF XY: 0.00802 AC XY: 594 AN XY: 74040

African (AFR) AF: 0.00203 AC: 84 AN: 41302

American (AMR) AF: 0.00623 AC: 95 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5124

South Asian (SAS) AF: 0.00126 AC: 6 AN: 4772

European-Finnish (FIN) AF: 0.00989 AC: 104 AN: 10516

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.0133 AC: 904 AN: 67830

Other (OTH) AF: 0.00669 AC: 14 AN: 2094

Alfa AF: 0.00717 Hom.: 4

Bravo AF: 0.00777

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	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	MPZ-related disorder (1)
-	1	-	Neuropathy, congenital hypomyelinating, 2 (1)
-	-	1	not provided (1)
-	-	1	Roussy-Lévy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.2
DANN	Benign	0.64
PhyloP100		-1.4
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs150182811; hg19: chr1-161275471;