Genetic Variant NM_000304.4:c.36C>A (chr17-15260692-G-T) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000304.4(PMP22):c.36C>A(p.His12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PMP22
NM_000304.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 1.14

Variant links:

Genes affected

PMP22 (HGNC:9118): (peripheral myelin protein 22) This gene encodes an integral membrane protein that is a major component of myelin in the peripheral nervous system. Studies suggest two alternately used promoters drive tissue-specific expression. Various mutations of this gene are causes of Charcot-Marie-Tooth disease Type IA, Dejerine-Sottas syndrome, and hereditary neuropathy with liability to pressure palsies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PMP22 links:

ENSG00000279660 (HGNC:):

ENSG00000279660 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a transmembrane_region Helical (size 29) in uniprot entity PMP22_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000304.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

PP5

Variant 17-15260692-G-T is Pathogenic according to our data. Variant chr17-15260692-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-15260692-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMP22	NM_000304.4 link	c.36C>A	p.His12Gln	missense_variant	Exon 2 of 5	ENST00000312280.9	NP_000295.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMP22	ENST00000312280.9 link	c.36C>A	p.His12Gln	missense_variant	Exon 2 of 5	1	NM_000304.4	ENSP00000308937.3		Q01453

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1401358

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691366

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Roussy-Lévy syndrome

Pathogenic:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3. -

Inborn genetic diseases

Pathogenic:1

Jan 27, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DEJERINE-SOTTAS SYNDROME, AUTOSOMAL DOMINANT

Pathogenic:1

Jan 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Charcot-Marie-Tooth disease, type I

Pathogenic:1

Jun 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 12 of the PMP22 protein (p.His12Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Dejerine-Sottas neuropathy (PMID: 7728152). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8434). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies have shown that this missense change affects PMP22 function (PMID: 10078969). For these reasons, this variant has been classified as Pathogenic. -

Dejerine-Sottas disease

Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.98

D;D;D;D;D;D;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.65

T;.;.;.;.;T;T

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.60

MutationAssessor

Pathogenic

3.4

M;M;M;.;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.5

.;D;D;.;D;.;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

.;D;D;.;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;.;D;.;D

Polyphen

0.55

P;P;P;.;.;.;.

Vest4

0.73

MutPred

0.79

Gain of catalytic residue at H12 (P = 0.0865);Gain of catalytic residue at H12 (P = 0.0865);Gain of catalytic residue at H12 (P = 0.0865);Gain of catalytic residue at H12 (P = 0.0865);Gain of catalytic residue at H12 (P = 0.0865);Gain of catalytic residue at H12 (P = 0.0865);Gain of catalytic residue at H12 (P = 0.0865);

MVP

0.91

MPC

0.60

ClinPred

0.99

GERP RS

3.5

Varity_R

0.92

gMVP

0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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