chr1-161307376-T-G

Variant names:

• chr1-161307376-T-G
• rs371856018
• NM_000530.8:c.116A>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PP2 PP3 PP5_Very_Strong

The NM_000530.8(MPZ):​c.116A>C​(p.His39Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000261054: Experimental studies have shown that this missense change affects MPZ function (PMID:18337304)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H39R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 2.74
• Publications: 12 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000261054: Experimental studies have shown that this missense change affects MPZ function (PMID: 18337304).; SCV000292950: Published functional studies demonstrate a damaging effect: partial loss of function (PMID: 18337304); SCV002626957: This alteration was found to be functionally abnormal in an assay of MPZ-mediated intercellular adhesion (Grandis, 2008).
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 20 uncertain in NM_000530.8
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 84 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.98749 (below the threshold of 3.09). Trascript score misZ: 1.4782 (below the threshold of 3.09). GenCC associations: The gene is linked to neuropathy, congenital hypomyelinating, 2, Charcot-Marie-Tooth disease, Charcot-Marie-Tooth disease type 1B, Charcot-Marie-Tooth disease dominant intermediate D, Charcot-Marie-Tooth disease type 2J, Charcot-Marie-Tooth disease type 3, Charcot-Marie-Tooth disease type 2I, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755
• PP5: Variant 1-161307376-T-G is Pathogenic according to our data. Variant chr1-161307376-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217232.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.116A>C	p.His39Pro	missense	Exon 2 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.116A>C	p.His39Pro	missense	Exon 2 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.116A>C	p.His39Pro	missense	Exon 2 of 6	ENSP00000432943.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.116A>C		non_coding_transcript_exon	Exon 2 of 7	ENSP00000431538.1	P25189-1
	MPZ	ENST00000672287.2		c.-473A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000499818.2	E9PL80

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
1	-	-	Charcot-Marie-Tooth disease type 1B (1)
1	-	-	Charcot-Marie-Tooth disease, type I (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	MPZ-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.12
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.27
Sift	Benign	0.11	T
Sift4G	Benign	0.20	T
Polyphen		0.0020	B
Vest4		0.79
MVP		0.94
MPC		1.6
ClinPred		0.97	D
GERP RS		5.3
PromoterAI		-0.0056	Neutral
Varity_R		0.95
gMVP		0.98
Mutation Taster		=19/81	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs371856018; hg19: chr1-161277166;