12-52676314-A-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_006121.4(KRT1):​c.1436T>A​(p.Ile479Asn) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• Conservation: PhyloP100: 9.25
• Publications: 1 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 10 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, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT1	NM_006121.4	c.1436T>A	p.Ile479Asn	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>A	p.Ile479Asn	missense_variant	Exon 7 of 9	1	NM_006121.4	ENSP00000252244.3
KRT1	ENST00000548765.1	n.510T>A		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		9.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.83		Gain of catalytic residue at L477 (P = 0.0038);
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.97
Mutation Taster		=5/95	disease causing

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;