rs59878153

Variant names:

• chr17-41571478-T-G
• rs59878153
• NM_000226.4:c.515A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000226.4(KRT9):​c.515A>C​(p.Gln172Pro) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRT9 NM_000226.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.0560
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000226.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 17-41571478-T-G is Pathogenic according to our data. Variant chr17-41571478-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2998.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT9	NM_000226.4	c.515A>C	p.Gln172Pro	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.515A>C	p.Gln172Pro	missense_variant	Exon 1 of 8	1	NM_000226.4	ENSP00000246662.4
KRT9	ENST00000588431.1	c.-185A>C		5_prime_UTR_variant	Exon 2 of 9	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:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Epidermolytic palmoplantar keratoderma, 1 Pathogenic:1

Jul 30, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.056
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.92	P
Vest4		0.72
MutPred		0.89		Gain of methylation at K170 (P = 0.1348);
MVP		0.90
MPC		0.42
ClinPred		0.93	D
GERP RS		-3.1
Varity_R		0.75
gMVP		0.98
Mutation Taster		=85/15	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs59878153; hg19: chr17-39727730;