12-52514985-A-T

Position:

• chr12-52514985-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000424.4(KRT5):​c.1730T>A​(p.Phe577Tyr) 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 3.27

Genes affected

KRT5 (HGNC:6442): (keratin 5) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the basal layer of the epidermis with family member KRT14. Mutations in these genes have been associated with a complex of diseases termed epidermolysis bullosa simplex. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

ACMG classification

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, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT5	NM_000424.4	c.1730T>A	p.Phe577Tyr	missense_variant	9/9	ENST00000252242.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT5	ENST00000252242.9	c.1730T>A	p.Phe577Tyr	missense_variant	9/9	1	NM_000424.4	P1
KRT5	ENST00000552952.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	0.90	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.44	N
REVEL	Uncertain	0.55
Sift	Benign	0.19	T
Sift4G	Benign	0.57	T
Polyphen		0.98	D
Vest4		0.76
MutPred		0.80		Gain of phosphorylation at F577 (P = 0.0503);
MVP		0.87
MPC		0.25
ClinPred		0.85	D
GERP RS		5.5
Varity_R		0.12
gMVP		0.56

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: rs267607442; hg19: chr12-52908769;