17-41571505-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000226.4(KRT9):c.488G>A(p.Arg163Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KRT9
NM_000226.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 4.13

Publications

9 publications found

Variant links:

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)

KRT9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr17-41571505-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3237488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 17-41571505-C-T is Pathogenic according to our data. Variant chr17-41571505-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3001.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 link	c.488G>A	p.Arg163Gln	missense_variant	Exon 1 of 8	ENST00000246662.9	NP_000217.2	P35527

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT9	ENST00000246662.9 link	c.488G>A	p.Arg163Gln	missense_variant	Exon 1 of 8	1	NM_000226.4	ENSP00000246662.4		P35527
KRT9	ENST00000588431.1 link	c.-189-23G>A		intron_variant	Intron 1 of 8	1		ENSP00000467932.1		K7EQQ3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74146

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41318

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Palmoplantar keratoderma, epidermolytic

Pathogenic:4

Dec 07, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 06, 2021

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PP1, PP3, PM1, PM2, PM5, PM6 -

Aug 10, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM1, PM2, PP2, PP3, PP5 -

Sep 01, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.87). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003001). A different missense change at the same codon (p.Arg163Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002997). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:2Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jun 20, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Located within the helix initiation motif in the 1A domain, a region intolerant to change (Chamcheu et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In silico analysis, which includes splice predictors, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22678789, 22584502, 7512862, 24862219, 22402445, 31074163, 22262370, 33914963, 19874353, 30666268) -

Jul 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 163 of the KRT9 protein (p.Arg163Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with epidermolytic palmoplantar keratoderma (PMID: 30666268, 33914963). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3001). 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 with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg163 amino acid residue in KRT9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22262370). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases

Pathogenic:1

May 05, 2017

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.10

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.91

MutationAssessor

Pathogenic

4.1

PhyloP100

4.1

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Benign

0.061

Polyphen

1.0

Vest4

0.91

MutPred

0.97

Loss of phosphorylation at S166 (P = 0.0655);

MVP

0.97

MPC

0.45

ClinPred

0.99

GERP RS

2.6

Varity_R

0.72

gMVP

0.87

Mutation Taster

=30/70

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.31

Position offset: -23

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over