rs58597584

chr17-41571524-T-Cchr17-41571524-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000226.4(KRT9):c.469A>G(p.Met157Val) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M157K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRT9 NM_000226.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.00

Genes affected

KRT9 (HGNC:6447): (keratin 9) This gene encodes the type I keratin 9, an intermediate filament chain expressed only in the terminally differentiated epidermis of palms and soles. Mutations in this gene cause epidermolytic palmoplantar keratoderma. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000226.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 17-41571524-T-C is Pathogenic according to our data. Variant chr17-41571524-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 3002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41571524-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT9	NM_000226.4	c.469A>G	p.Met157Val	missense_variant	1/8	ENST00000246662.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT9	ENST00000246662.9	c.469A>G	p.Met157Val	missense_variant	1/8	1	NM_000226.4	P1
KRT9	ENST00000588431.1	c.-189-42A>G		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2017	The M157V variant in the KRT9 gene has been reported previously using alternate nomenclature (M156V) in association with epidermolytic palmoplantar keratoderma (EPPK) (Hennies et al., 1994; Covello et al., 1998; Rugg et al., 2002). The M157V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The M157V variant is a conservative amino acid substitution and occurs within a known mutational hotspot region (helix initiation motif) that is highly conserved across all species and among all members of the keratin family. Missense variants at the same residue (M157R, M157K, M157T) and in nearby residues (L160V, L160F, L160P, N161Y, N161H, N161S, N161I, N161K) have been reported in the Human Gene Mutation Database in association with EPPK (Stenson et al., 2014), supporting the functional importance of this region of the protein. It is well established that keratin gene mutations affecting the residues at the ends of the central rod domains of the keratin proteins (helix initiation and termination motifs) interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility and/or hyperkeratosis (Chamcheu et al., 2011). Therefore, we interpret M157V as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 15, 2023	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRT9 protein function. ClinVar contains an entry for this variant (Variation ID: 3002). This variant is also known as c.466A>G (p.Met156Val); c.532A>G (p.Met156Val). This missense change has been observed in individuals with epidermolytic palmoplantar keratoderma (PMID: 7516304, 9856842). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 157 of the KRT9 protein (p.Met157Val). -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Epidermolytic palmoplantar keratoderma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 30, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.5	H
MutationTaster	Benign	0.44	A;A
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		0.83	P
Vest4		0.91
MutPred		0.90		Loss of disorder (P = 0.111);
MVP		0.96
MPC		0.42
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.90
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

Other links and lift over

dbSNP: rs58597584; hg19: chr17-39727776;