rs144841836

Variant names:

• chr1-161309882-G-A
• rs144841836
• NM_000530.8:c.24C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000530.8(MPZ):​c.24C>T​(p.Ser8Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00033 in 1,589,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: MPZ NM_000530.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.43
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 1-161309882-G-A is Benign according to our data. Variant chr1-161309882-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 462791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000349 (53/152034) while in subpopulation NFE AF = 0.000662 (45/68020). AF 95% confidence interval is 0.000508. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 53 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.24C>T	p.Ser8Ser	synonymous	Exon 1 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.24C>T	p.Ser8Ser	synonymous	Exon 1 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.24C>T	p.Ser8Ser	synonymous	Exon 1 of 6	ENSP00000432943.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.24C>T		non_coding_transcript_exon	Exon 1 of 7	ENSP00000431538.1	P25189-1
	MPZ	ENST00000672602.2		c.24C>T	p.Ser8Ser	synonymous	Exon 1 of 6	ENSP00000500814.2	A0A5F9ZI26

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 152034 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000246 AC: 51 AN: 207406 AF XY: 0.000261

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000699

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000222

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.000385

GnomAD4 exome AF: 0.000328 AC: 471 AN: 1437338 Hom.: 0 Cov.: 30 AF XY: 0.000341 AC XY: 243 AN XY: 712104

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.000101 AC: 4 AN: 39620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25496

East Asian (EAS) AF: 0.00 AC: 0 AN: 38980

South Asian (SAS) AF: 0.00 AC: 0 AN: 82028

European-Finnish (FIN) AF: 0.000369 AC: 19 AN: 51554

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5706

European-Non Finnish (NFE) AF: 0.000396 AC: 436 AN: 1101028

Other (OTH) AF: 0.000185 AC: 11 AN: 59566

GnomAD4 genome AF: 0.000349 AC: 53 AN: 152034 Hom.: 0 Cov.: 28 AF XY: 0.000364 AC XY: 27 AN XY: 74274

African (AFR) AF: 0.0000242 AC: 1 AN: 41374

American (AMR) AF: 0.000131 AC: 2 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000457 Hom.: 0

Bravo AF: 0.000223

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease, type I (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.1
DANN	Benign	0.73
PhyloP100		1.4
PromoterAI		-0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
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: rs144841836; hg19: chr1-161279672;