17-41518653-C-T

Position:

• chr17-41518653-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000254043.8(KRT15):​c.175G>A​(p.Gly59Arg) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: KRT15 ENST00000254043.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36485493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT15	NM_002275.4	c.175G>A	p.Gly59Arg	missense_variant	1/8	ENST00000254043.8	NP_002266.3
KRT15	XM_011524784.4	c.175G>A	p.Gly59Arg	missense_variant	1/8		XP_011523086.1
KRT15	XM_017024614.3	c.175G>A	p.Gly59Arg	missense_variant	1/8		XP_016880103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT15	ENST00000254043.8	c.175G>A	p.Gly59Arg	missense_variant	1/8	1	NM_002275.4	ENSP00000254043	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 28

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2023

The c.175G>A (p.G59R) alteration is located in exon 1 (coding exon 1) of the KRT15 gene. This alteration results from a G to A substitution at nucleotide position 175, causing the glycine (G) at amino acid position 59 to be replaced by an arginine (R). 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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.27	T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.54	.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.61	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.64
Sift	Benign	0.35	T;T
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.72	P;P
Vest4		0.48
MutPred		0.44		Gain of methylation at G59 (P = 0.0017);Gain of methylation at G59 (P = 0.0017);
MVP		0.81
MPC		0.13
ClinPred		0.76	D
GERP RS		3.6
Varity_R		0.18
gMVP		0.76

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

Other links and lift over

dbSNP: rs762594315; hg19: chr17-39674905;