rs57695159

Positions:

• chr12-52679867-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_006121.4(KRT1):​c.482T>C​(p.Leu161Pro) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L161F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRT1 NM_006121.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.55

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 12-52679867-A-G is Pathogenic according to our data. Variant chr12-52679867-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 15908.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-52679867-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT1	NM_006121.4	c.482T>C	p.Leu161Pro	missense_variant	1/9	ENST00000252244.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT1	ENST00000252244.3	c.482T>C	p.Leu161Pro	missense_variant	1/9	1	NM_006121.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 20, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KRT1 function (PMID: 1381288). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KRT1 protein function. ClinVar contains an entry for this variant (Variation ID: 15908). This variant is also known as leucine to proline amino acid substitution at codon 160. This missense change has been observed in individual(s) with epidermolytic ichthyosis (PMID: 1284546, 1381288). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 161 of the KRT1 protein (p.Leu161Pro). -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Epidermolytic ichthyosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 04, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.74		Gain of catalytic residue at L162 (P = 0);
MVP		0.95
MPC		1.2
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.96
gMVP		0.98

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: rs57695159; hg19: chr12-53073651;