rs59616921

Positions:

• chr17-41571506-G-A

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.487C>T​(p.Arg163Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R163P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRT9 NM_000226.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• Conservation: PhyloP100: 3.51

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 region_of_interest Coil 1A (size 35) in uniprot entity K1C9_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) 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, 0.995
• PP5: Variant 17-41571506-G-A is Pathogenic according to our data. Variant chr17-41571506-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-41571506-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT9	NM_000226.4	c.487C>T	p.Arg163Trp	missense_variant	1/8	ENST00000246662.9	NP_000217.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT9	ENST00000246662.9	c.487C>T	p.Arg163Trp	missense_variant	1/8	1	NM_000226.4	ENSP00000246662	P1
KRT9	ENST00000588431.1	c.-189-24C>T		intron_variant		1		ENSP00000467932

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2023	Located within the helix initiation motif within the 1A region of the rod domain, which is a well-known mutation hotspot intolerant to change; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19223272, 25299193, 23278372, 22262370, 27864007, 30666268, 10844507, 15564199, 33914963, 7512862) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2022	ClinVar contains an entry for this variant (Variation ID: 2997). This missense change has been observed in individuals with epidermolytic palmoplantar keratoderma (PMID: 22262370). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 163 of the KRT9 protein (p.Arg163Trp). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 18, 2023	- -

Palmoplantar keratoderma, epidermolytic Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Aug 10, 2021	This sequence change in KRT9 is predicted to replace arginine with tryptophan at codon 163 (p.(Arg163Trp)). The arginine residue is highly conserved (100 vertebrates, UCSC), and is an invariant residue in human type 1 keratins in the coil 1A alpha-helical segment of the intermediate filament rod domain (PMID: 7512862). There is a large physicochemical difference between arginine and tryptophan. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in multiple probands with epidermolytic palmoplantar keratoderma, and segregates with the disease in multiple families (PMID: 7512862, 7523529). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Moderate, PM1, PM2_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 19, 2023	Criteria applied: PM5_STR,PP1_STR,PS4_MOD,PM1,PM2_SUP,PP3 -

Epidermolytic palmoplantar keratoderma, 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense c.487C>T(p.Arg163Trp) variant in KRT9 gene has been reported previously in heterozygous state in multiple individuals affected with epidermolytic palmoplantar keratoderma (Wang P, et al., 2016; Liu WT, et al., 2012; Chiu HC, et al., 2007). This variant has also been observed to segregate with disease in related individuals. The p.Arg163Trp variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Multiple lines of computational evidences (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 163 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Palmoplantar keratoderma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	0.57	A;A
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.97		Loss of disorder (P = 0.011);
MVP		0.98
MPC		0.43
ClinPred		1.0	D
GERP RS		0.80
Varity_R		0.80
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs59616921; hg19: chr17-39727758;