rs104894625

chr17-15260663-G-Achr17-15260663-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PP3_Moderate PP5

The NM_000304.4(PMP22):c.65C>T(p.Ser22Phe) variant causes a missense change. 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. S22P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMP22 NM_000304.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 5.81

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000304.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866
• PP5: Variant 17-15260663-G-A is Pathogenic according to our data. Variant chr17-15260663-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8445.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-15260663-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMP22	NM_000304.4	c.65C>T	p.Ser22Phe	missense_variant	2/5	ENST00000312280.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMP22	ENST00000312280.9	c.65C>T	p.Ser22Phe	missense_variant	2/5	1	NM_000304.4	P1
	ENST00000623265.1	n.151G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1400130 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 690666

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.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Charcot-Marie-Tooth disease, type IA Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2004	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hereditary liability to pressure palsies Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Pathogenic	33
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.96	D;D;D;D;D;D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.85	D;.;.;.;.;T;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.9	M;M;M;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.0050	D;D;D;.;D;.;D
Polyphen		0.96	D;D;D;.;.;.;.
Vest4		0.87
MutPred		0.71		Loss of glycosylation at S22 (P = 0.0174);Loss of glycosylation at S22 (P = 0.0174);Loss of glycosylation at S22 (P = 0.0174);Loss of glycosylation at S22 (P = 0.0174);Loss of glycosylation at S22 (P = 0.0174);Loss of glycosylation at S22 (P = 0.0174);Loss of glycosylation at S22 (P = 0.0174);
MVP		0.96
MPC		1.4
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.52
gMVP		0.98

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

Other links and lift over

dbSNP: rs104894625; hg19: chr17-15163980;