rs28933089

Variant names:

• chr17-41624214-A-G
• rs28933089
• NM_000422.3:c.296T>C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000422.3(KRT17):​c.296T>C​(p.Leu99Pro) 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 (★).

• 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: 8.97

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 10 ACMG points.

• PM1: In a region_of_interest Coil 1A (size 36) in uniprot entity K1C17_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_000422.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-41624214-A-G is Pathogenic according to our data. Variant chr17-41624214-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 14598.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-41624214-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT17	NM_000422.3	c.296T>C	p.Leu99Pro	missense_variant	Exon 1 of 8	ENST00000311208.13	NP_000413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT17	ENST00000311208.13	c.296T>C	p.Leu99Pro	missense_variant	Exon 1 of 8	1	NM_000422.3	ENSP00000308452.8

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

Jan 16, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Located in the highly conserved helix initiation motif of the alpha-helical rod domain, which is intolerant to change; variants in this motif interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility and/or hyperkeratosis (PMID: 21176769); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29784039, 21287500, 33486795, 11886499, 31823354, 28794556, 34116063, 24611874, 19120334, 21176769) -

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Pachyonychia congenita 2 Pathogenic:1

Dec 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;T
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.5	.;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;.
Polyphen		1.0	D;D;.
Vest4		1.0
MutPred		0.97		Loss of stability (P = 0.0123);Loss of stability (P = 0.0123);.;
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.97
gMVP		0.95

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: rs28933089; hg19: chr17-39780466;