rs57837128

Variant names:

• chr12-52676314-A-G
• rs57837128
• NM_006121.4:c.1436T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-52676314-A-G
• chr12-52676314-A-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_006121.4(KRT1):​c.1436T>C​(p.Ile479Thr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I479F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT1 NM_006121.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 9.25
• Publications: 16 publications found

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]

KRT1 Gene-Disease associations (from GenCC):

• annular epidermolytic ichthyosis

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, PanelApp Australia
• ichthyosis hystrix of Curth-Macklin

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, PanelApp Australia
• diffuse nonepidermolytic palmoplantar keratoderma

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• epidermolytic ichthyosis

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Illumina, Orphanet, Genomics England PanelApp, PanelApp Australia
• ichthyosis, annular epidermolytic 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ichthyosis, annular epidermolytic, 2

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• congenital reticular ichthyosiform erythroderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive congenital ichthyosis 11

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_006121.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-52676315-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 15912.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 12-52676314-A-G is Pathogenic according to our data. Variant chr12-52676314-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT1	NM_006121.4	c.1436T>C	p.Ile479Thr	missense_variant	Exon 7 of 9	ENST00000252244.3	NP_006112.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT1	ENST00000252244.3	c.1436T>C	p.Ile479Thr	missense_variant	Exon 7 of 9	1	NM_006121.4	ENSP00000252244.3
KRT1	ENST00000548765.1	n.510T>C		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Located in the highly conserved helix termination motif of the alpha-helical rod domain, which is intolerant to change; variants in this motif interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility and/or hyperkeratosis (PMID: 21176769, 21271994, 26176760); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10688370, 27421141, 27617465, 32588446, 10053007, 26581228, 26945532, 23623204, 21271994, 25904304, 30152556, 34188299, 32666929, 21176769, 26176760, 36656063, 22250628, 15214894) -

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 479 of the KRT1 protein (p.Ile479Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with KRT1-related conditions (PMID: 10053007, 15214894, 22250628, 30152556). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 15911). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Ichthyosis, annular epidermolytic, 2 Pathogenic:1

Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

KRT1-related disorder Pathogenic:1

Jun 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KRT1 c.1436T>C variant is predicted to result in the amino acid substitution p.Ile479Thr. This variant has been reported and shown to co-segregate with disease in multiple individuals and families with epidermolytic ichthyosis (Sybert et al. 1999. PubMed ID: 10053007; Arin et al. 2000. PubMed ID: 10688370; Terron-Kwiatkowski et al. 2004. PubMed ID: 15214894; Zeng et al. 2012. PubMed ID: 22250628; Murase et al. 2020. PubMed ID: 32588446; Liang et al. 2020. PubMed ID: 32666929). It has also been reported to have arisen de novo in at least two affected individuals (Sybert et al. 1999. PubMed ID: 10053007; Chen et al. 2021. PubMed ID: 34188299). In vitro studies have shown the p.Ile479Thr variant led to the formation of mutant keratin aggregates and significantly increased levels of multiple inflammatory markers relative to wild type protein (Ansai et al. 2023. PubMed ID: 36656063). This variant has not been reported in the gnomAD database, indicating this variant is rare. Another missense variant at the same amino acid residue (p.Ile479Phe) has been reported and shown to co-segregate with disease in at least two families with KRT1-related disease (Sybert et al. 1999. PubMed ID: 10053007; Michael et al. 1999. PubMed ID: 10597140). Taken together, the p.Ile479Thr variant is interpreted as pathogenic. -

Annular epidermolytic ichthyosis Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.I479T in KRT1 (NM_006121.4) has been previously reported in patients with cyclic ichthyosis with epidermolytic hyperkeratosis as well as in patients with epidermolytic palmoplantar keratoderma ( Hotz et al., 2016; TerronKwiatkowski et al., 2004). The variant has been submitted to ClinVar as Pathogenic.No functional studies have been performed. The p.I479T variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.I479T missense variant is predicted to be damaging by both SIFT and PolyPhen2. The isoleucine residue at codon 479 of KRT1 is conserved in all mammalian species. The nucleotide c.1436 in KRT1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.86		Gain of catalytic residue at L477 (P = 0.0028);
MVP		0.99
MPC		0.98
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.89
gMVP		0.89
Mutation Taster		=5/95	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs57837128; hg19: chr12-53070098;