rs58597584

Variant names:

• chr17-41571524-T-C
• rs58597584
• NM_000226.4:c.469A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-41571524-T-C
• chr17-41571524-T-G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 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. M157R) 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
• Publications: 5 publications found

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]

KRT9 Gene-Disease associations (from GenCC):

• epidermolytic palmoplantar keratoderma, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000226.4
• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 3002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT9	NM_000226.4	c.469A>G	p.Met157Val	missense_variant	Exon 1 of 8	ENST00000246662.9	NP_000217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT9	ENST00000246662.9	c.469A>G	p.Met157Val	missense_variant	Exon 1 of 8	1	NM_000226.4	ENSP00000246662.4
KRT9	ENST00000588431.1	c.-189-42A>G		intron_variant	Intron 1 of 8	1		ENSP00000467932.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

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

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 13, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Epidermolytic palmoplantar keratoderma, 1 Pathogenic:1

Jul 30, 2003

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	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
PhyloP100		5.0
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
Mutation Taster		=32/68	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs58597584; hg19: chr17-39727776;