rs57959072

Positions:

• chr12-52679885-A-C
• chr12-52679885-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM2 PM5 PP3_Strong

The NM_006121.4(KRT1):​c.464T>G​(p.Val155Gly) variant causes a missense change involving the alteration of a 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V155D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRT1 NM_006121.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.30

Genes affected

KRT1 (HGNC:6412): (keratin 1) 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 spinous and granular layers of the epidermis with family member KRT10 and mutations in these genes have been associated with bullous congenital ichthyosiform erythroderma. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_006121.4 (KRT1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-52679885-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 15913.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT1	NM_006121.4	c.464T>G	p.Val155Gly	missense_variant	1/9	ENST00000252244.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT1	ENST00000252244.3	c.464T>G	p.Val155Gly	missense_variant	1/9	1	NM_006121.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

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

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.81		Gain of catalytic residue at Q153 (P = 0);
MVP		0.93
MPC		1.1
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.93
gMVP		0.99

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: rs57959072; hg19: chr12-53073669;