NM_000530.8:c.*360C>G

Variant names:

• chr1-161305516-G-C
• rs6682046
• NM_000530.8:c.*360C>G

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.*360C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 277,242 control chromosomes in the GnomAD database, including 3 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 0.0028 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: MPZ NM_000530.8 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.502
• 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, 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=-0.8).
• BP6: Variant 1-161305516-G-C is Benign according to our data. Variant chr1-161305516-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 876416.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00279 (425/152200) while in subpopulation AFR AF = 0.00959 (398/41518). AF 95% confidence interval is 0.00881. There are 2 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 425 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.*360C>G		3_prime_UTR	Exon 6 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.*168C>G		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.*360C>G		3_prime_UTR	Exon 6 of 6	ENSP00000432943.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.*342+18C>G		intron	N/A	ENSP00000431538.1	P25189-1
	MPZ	ENST00000672602.2		c.*168C>G		3_prime_UTR	Exon 6 of 6	ENSP00000500814.2	A0A5F9ZI26

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 425 AN: 152082 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00961

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.000352 AC: 44 AN: 125042 Hom.: 1 Cov.: 0 AF XY: 0.000244 AC XY: 16 AN XY: 65468

African (AFR) AF: 0.00640 AC: 23 AN: 3596

American (AMR) AF: 0.00196 AC: 10 AN: 5092

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3656

East Asian (EAS) AF: 0.000308 AC: 2 AN: 6484

South Asian (SAS) AF: 0.00 AC: 0 AN: 15092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7296

Middle Eastern (MID) AF: 0.00370 AC: 2 AN: 540

European-Non Finnish (NFE) AF: 0.0000395 AC: 3 AN: 75944

Other (OTH) AF: 0.000545 AC: 4 AN: 7342

GnomAD4 genome AF: 0.00279 AC: 425 AN: 152200 Hom.: 2 Cov.: 30 AF XY: 0.00273 AC XY: 203 AN XY: 74402

African (AFR) AF: 0.00959 AC: 398 AN: 41518

American (AMR) AF: 0.00131 AC: 20 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.0000696 Hom.: 0

Bravo AF: 0.00318

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	-	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	-0.80
CADD	Benign	9.0
DANN	Benign	0.77
PhyloP100		-0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs6682046; hg19: chr1-161275306;