rs28928899

chr17-41624226-A-Gchr17-41624226-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000422.3(KRT17):c.284T>C(p.Leu95Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L95Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT17 NM_000422.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.32

Genes affected

KRT17 (HGNC:6427): (keratin 17) This gene encodes the type I intermediate filament chain keratin 17, expressed in nail bed, hair follicle, sebaceous glands, and other epidermal appendages. Mutations in this gene lead to Jackson-Lawler type pachyonychia congenita and steatocystoma multiplex. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000422.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-41624226-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 14595.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-41624226-A-G is Pathogenic according to our data. Variant chr17-41624226-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 14596.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-41624226-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT17	NM_000422.3	c.284T>C	p.Leu95Pro	missense_variant	1/8	ENST00000311208.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT17	ENST00000311208.13	c.284T>C	p.Leu95Pro	missense_variant	1/8	1	NM_000422.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2015	The L95P variant has been reported previously is a patient with sporadic pachyonychia congenita(Terrinoni et al. 2001). The L95P variant is a semi-conservative amino acid change and located in ahighly conserved region coding for the helix initiation motif of keratin 17, a known hotspot.Other pathogenic variants in this and neighboring codons (L95Q, R94H/P/G/C/Q) are published accordingto the Human Gene Mutation Database (Stenson et al. 2014). Moreover, L95P was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret L95P as a pathogenic variant. -

Pachyonychia congenita 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.98		Loss of stability (P = 0.0066);Loss of stability (P = 0.0066);.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.97

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: rs28928899; hg19: chr17-39780478;