17-41515499-C-T

Position:

chr17-41515499-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002275.4(KRT15):c.1220G>A(p.Arg407His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,566 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

KRT15
NM_002275.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99

Variant links:

Genes affected

KRT15 (HGNC:6421): (keratin 15) The protein encoded by this gene is a member of the keratin gene family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. Most of the type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains and are clustered in a region on chromosome 17q21.2. [provided by RefSeq, Jul 2008]

KRT15 links:

KRT15 (HGNC:):

KRT15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.884

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT15	NM_002275.4 linkuse as main transcript	c.1220G>A	p.Arg407His	missense_variant	6/8	ENST00000254043.8	NP_002266.3	P19012-1B3KVF5
KRT15	XM_011524784.4 linkuse as main transcript	c.1241G>A	p.Arg414His	missense_variant	6/8		XP_011523086.1
KRT15	XM_017024614.3 linkuse as main transcript	c.1241G>A	p.Arg414His	missense_variant	6/8		XP_016880103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KRT15	ENST00000254043.8 linkuse as main transcript	c.1220G>A	p.Arg407His	missense_variant	6/8	1	NM_002275.4	ENSP00000254043.3	P19012-1
KRT15	ENST00000393974.7 linkuse as main transcript	c.725G>A	p.Arg242His	missense_variant	5/7	1		ENSP00000377544.3	A8MT21
KRT15	ENST00000393976.6 linkuse as main transcript	c.1220G>A	p.Arg407His	missense_variant	8/10	5		ENSP00000377546.1	P19012-1
KRT15	ENST00000474031.5 linkuse as main transcript	n.861G>A		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

250998

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000470

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461382

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000151

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2022

The c.1220G>A (p.R407H) alteration is located in exon 6 (coding exon 6) of the KRT15 gene. This alteration results from a G to A substitution at nucleotide position 1220, causing the arginine (R) at amino acid position 407 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.036

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;D;D

Eigen

Benign

0.17

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

.;D;D

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.8

L;.;L

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Uncertain

0.57

Sift

Benign

0.062

T;T;T

Sift4G

Benign

0.080

T;T;T

Polyphen

0.54

P;P;P

Vest4

0.33

MutPred

0.88

Gain of catalytic residue at L409 (P = 0.0724);.;Gain of catalytic residue at L409 (P = 0.0724);

MVP

0.87

MPC

0.15

ClinPred

0.40

GERP RS

2.7

Varity_R

0.22

gMVP

0.79

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over