1-161304965-T-TTCTC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000530.8(MPZ):c.*910_*911insGAGA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 149,882 control chromosomes in the GnomAD database, including 1,305 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1302 hom., cov: 26)
  • Exomes 𝑓: 0.12 (3 hom.)
• Consequence: MPZ NM_000530.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.360

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-161304965-T-TTCTC is Benign according to our data. Variant chr1-161304965-T-TTCTC is described in ClinVar as [Benign]. Clinvar id is 293302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPZ	NM_000530.8	c.*910_*911insGAGA		3_prime_UTR_variant	6/6	ENST00000533357.5
MPZ	NM_001315491.2	c.*718_*719insGAGA		3_prime_UTR_variant	6/6
MPZ	XM_017001321.3	c.676-625_676-624insGAGA		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPZ	ENST00000533357.5	c.*910_*911insGAGA		3_prime_UTR_variant	6/6	1	NM_000530.8	P1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19335 AN: 149126 Hom.: 1292 Cov.: 26

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.0784

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.138

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.149

GnomAD4 exome AF: 0.123 AC: 78 AN: 636 Hom.: 3 Cov.: 0 AF XY: 0.139 AC XY: 53 AN XY: 380

Gnomad4 AFR exome AF: 0.00

Gnomad4 EAS exome AF: 0.164

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.0800

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.130 AC: 19369 AN: 149246 Hom.: 1302 Cov.: 26 AF XY: 0.129 AC XY: 9372 AN XY: 72720

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.0789

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.148

Asia WGS AF: 0.0890 AC: 310 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease type 4E Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Roussy-Lévy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Charcot-Marie-Tooth disease, type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Charcot-Marie-Tooth, Intermediate Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs149030537; hg19: chr1-161274755;