rs16832786

Variant names:

• chr1-161305115-T-C
• rs16832786
• NM_000530.8:c.*761A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000530.8(MPZ):​c.*761A>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 0.129 in 152,666 control chromosomes in the GnomAD database, including 1,561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1558 hom., cov: 30)
  • Exomes 𝑓: 0.072 (3 hom.)
• Consequence: MPZ NM_000530.8 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.14
• Publications: 5 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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-161305115-T-C is Benign according to our data. Variant chr1-161305115-T-C is described in ClinVar as Benign. ClinVar VariationId is 293304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

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.*761A>G		3_prime_UTR	Exon 6 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.*569A>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.*761A>G		3_prime_UTR	Exon 6 of 6	ENSP00000432943.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.*517A>G		non_coding_transcript_exon	Exon 7 of 7	ENSP00000431538.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.*517A>G		3_prime_UTR	Exon 7 of 7	ENSP00000431538.1	P25189-1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19614 AN: 151826 Hom.: 1547 Cov.: 30

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0842

Gnomad ASJ AF: 0.0727

Gnomad EAS AF: 0.0412

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.0554

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.111

GnomAD4 exome AF: 0.0720 AC: 52 AN: 722 Hom.: 3 Cov.: 0 AF XY: 0.0658 AC XY: 30 AN XY: 456

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.102 AC: 10 AN: 98

South Asian (SAS) AF: 0.167 AC: 2 AN: 12

European-Finnish (FIN) AF: 0.0628 AC: 27 AN: 430

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0617 AC: 10 AN: 162

Other (OTH) AF: 0.0714 AC: 1 AN: 14

GnomAD4 genome AF: 0.129 AC: 19653 AN: 151944 Hom.: 1558 Cov.: 30 AF XY: 0.127 AC XY: 9441 AN XY: 74262

African (AFR) AF: 0.221 AC: 9143 AN: 41382

American (AMR) AF: 0.0841 AC: 1284 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0727 AC: 252 AN: 3468

East Asian (EAS) AF: 0.0415 AC: 215 AN: 5176

South Asian (SAS) AF: 0.150 AC: 719 AN: 4804

European-Finnish (FIN) AF: 0.0554 AC: 585 AN: 10558

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7079 AN: 67966

Other (OTH) AF: 0.110 AC: 232 AN: 2116

Alfa AF: 0.114 Hom.: 1605

Bravo AF: 0.132

Asia WGS AF: 0.112 AC: 390 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.52
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs16832786; hg19: chr1-161274905;