rs121913601

Variant names:

• chr1-161307259-G-A
• rs121913601
• NM_000530.8:c.233C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-161307259-G-A
• chr1-161307259-G-C

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.233C>T​(p.Ser78Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. S78W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MPZ NM_000530.8 missense, splice_region
• Scores: Splicing: ADA: 0.9800
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.75
• Publications: 26 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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 26 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 chr1-161307259-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 411669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-161307259-G-A is Pathogenic according to our data. Variant chr1-161307259-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14188.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.233C>T	p.Ser78Leu	missense splice_region	Exon 2 of 6	NP_000521.2	P25189-1
	MPZ	NM_001315491.2		c.233C>T	p.Ser78Leu	missense splice_region	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.233C>T	p.Ser78Leu	missense splice_region	Exon 2 of 6	ENSP00000432943.1	P25189-1
	MPZ	ENST00000463290.5	TSL:1	n.233C>T		splice_region non_coding_transcript_exon	Exon 2 of 7	ENSP00000431538.1	P25189-1
	MPZ	ENST00000672287.2		c.-356C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000499818.2	E9PL80

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00197 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	not provided (5)
1	-	-	Charcot-Marie-Tooth disease (1)
1	-	-	CHARCOT-MARIE-TOOTH DISEASE, TYPE 1B, WITH FOCALLY FOLDED MYELIN SHEATHS (1)
1	-	-	Charcot-Marie-Tooth disease, type I (1)
1	-	-	Hereditary neuropathy or pain disorder (1)
1	-	-	MPZ-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.3	L
PhyloP100		8.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.51		Loss of disorder (P = 0.045)
MVP		0.95
MPC		1.4
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		0.024	Neutral
Varity_R		0.80
gMVP		0.98
Mutation Taster		=162/138	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.79
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: rs121913601; hg19: chr1-161277049; COSMIC: COSV105205610; COSMIC: COSV105205610;