rs104894627

Positions:

• chr17-15259162-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000304.4(PMP22):​c.110A>T​(p.Asp37Val) variant causes a missense change. 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D37H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.18

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain Peripheral myelin protein 22 (size 159) in uniprot entity PMP22_HUMAN there are 98 pathogenic changes around while only 10 benign (91%) in NM_000304.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 17-15259162-T-A is Pathogenic according to our data. Variant chr17-15259162-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 8442.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-15259162-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMP22	NM_000304.4	c.110A>T	p.Asp37Val	missense_variant	3/5	ENST00000312280.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMP22	ENST00000312280.9	c.110A>T	p.Asp37Val	missense_variant	3/5	1	NM_000304.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease, type 1a, with focally folded myelin sheaths Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 11, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.98	D;D;D;D;D;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;.;.;.;.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.2	M;M;M;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.56	T
Sift4G	Uncertain	0.0030	D;D;D;.;D;.;D
Polyphen		1.0	D;D;D;.;.;.;.
Vest4		0.92
MutPred		0.92		Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);Loss of disorder (P = 0.0521);
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.85
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs104894627; hg19: chr17-15162479;