rs267607431

Positions:

• chr12-52791248-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_057088.3(KRT3):​c.1493A>T​(p.Glu498Val) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E498K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT3 NM_057088.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.92

Genes affected

KRT3 (HGNC:6440): (keratin 3) 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 corneal epithelium with family member KRT12 and mutations in these genes have been associated with Meesmann's Corneal Dystrophy. 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 11 ACMG points.

• PM1: In a region_of_interest Coil 2 (size 138) in uniprot entity K2C3_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_057088.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-52791249-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1213856.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 12-52791248-T-A is Pathogenic according to our data. Variant chr12-52791248-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 66748.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT3	NM_057088.3	c.1493A>T	p.Glu498Val	missense_variant	7/9	ENST00000417996.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT3	ENST00000417996.2	c.1493A>T	p.Glu498Val	missense_variant	7/9	1	NM_057088.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Corneal dystrophy, Meesmann, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 15, 2008

- -

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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.82		Gain of catalytic residue at D496 (P = 0.0488);
MVP		1.0
MPC		0.65
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.93
gMVP		0.96

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: rs267607431; hg19: chr12-53185032;