rs57536312

Variant names:

• chr17-41571510-A-T
• rs57536312
• NM_000226.4:c.483T>A

Your query was ambiguous. Multiple possible variants found:

• chr17-41571510-A-T
• chr17-41571510-A-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000226.4(KRT9):​c.483T>A​(p.Asn161Lys) 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. N161H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRT9 NM_000226.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: -0.917
• 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr17-41571511-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 3009.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 17-41571510-A-T is Pathogenic according to our data. Variant chr17-41571510-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000226.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT9	NM_000226.4	MANE Select	c.483T>A	p.Asn161Lys	missense	Exon 1 of 8	NP_000217.2	P35527

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT9	ENST00000246662.9	TSL:1 MANE Select	c.483T>A	p.Asn161Lys	missense	Exon 1 of 8	ENSP00000246662.4	P35527
	KRT9	ENST00000588431.1	TSL:1	c.-189-28T>A		intron	N/A	ENSP00000467932.1	K7EQQ3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Epidermolytic palmoplantar keratoderma, 1 (2)
1	-	-	Palmoplantar keratoderma, epidermolytic (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		-0.92
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.97		Gain of ubiquitination at N161 (P = 0.0211)
MVP		0.95
MPC		0.44
ClinPred		0.90	D
GERP RS		-1.5
Varity_R		0.70
gMVP		0.99
Mutation Taster		=26/74	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs57536312; hg19: chr17-39727762;