1-161306738-A-T

Variant names:

• chr1-161306738-A-T
• rs572010627
• NM_000530.8:c.418T>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_000530.8(MPZ):​c.418T>A​(p.Ser140Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,880 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S140P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MPZ NM_000530.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 3.03
• Publications: 7 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 16 ACMG points.

• PM1: In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_000530.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-161306737-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 531698.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 Charcot-Marie-Tooth disease dominant intermediate D, Charcot-Marie-Tooth disease type 1B, autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain, Charcot-Marie-Tooth disease type 2J, neuropathy, congenital hypomyelinating, 2, Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 3, Charcot-Marie-Tooth disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776
• PP5: Variant 1-161306738-A-T is Pathogenic according to our data. Variant chr1-161306738-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 447730.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.418T>A	p.Ser140Thr	missense	Exon 3 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.418T>A	p.Ser140Thr	missense	Exon 3 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.418T>A	p.Ser140Thr	missense	Exon 3 of 6	ENSP00000432943.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.418T>A		non_coding_transcript_exon	Exon 3 of 7	ENSP00000431538.1	P25189-1
	MPZ	ENST00000672602.2		c.418T>A	p.Ser140Thr	missense	Exon 3 of 6	ENSP00000500814.2	A0A5F9ZI26

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251496 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727238

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 29

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.7	L
PhyloP100		3.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.69
Sift	Benign	0.075	T
Sift4G	Benign	0.18	T
Polyphen		0.67	P
Vest4		0.56
MutPred		0.72		Loss of ubiquitination at K138 (P = 0.0877)
MVP		0.97
MPC		0.84
ClinPred		0.42	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.96
Mutation Taster		=4/96	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: rs572010627; hg19: chr1-161276528;