Genetic Variant NM_005556.4:c.263G>T (chr12-52233559-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005556.4(KRT7):c.263G>T(p.Arg88Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KRT7
NM_005556.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.06

Variant links:

Genes affected

KRT7 (HGNC:6445): (keratin 7) 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 simple epithelia lining the cavities of the internal organs and in the gland ducts and blood vessels. The genes encoding the type II cytokeratins are clustered in a region of chromosome 12q12-q13. Alternative splicing may result in several transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

KRT7 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT7	NM_005556.4 link	c.263G>T	p.Arg88Leu	missense_variant	Exon 1 of 9	ENST00000331817.6	NP_005547.3	P08729
KRT7	XM_011538325.3 link	c.263G>T	p.Arg88Leu	missense_variant	Exon 1 of 8		XP_011536627.1
KRT7	XM_047428827.1 link	c.263G>T	p.Arg88Leu	missense_variant	Exon 1 of 7		XP_047284783.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRT7	ENST00000331817.6 link	c.263G>T	p.Arg88Leu	missense_variant	Exon 1 of 9	1	NM_005556.4	ENSP00000329243.5	P08729
KRT7	ENST00000547613.1 link	n.-33G>T		upstream_gene_variant		3
KRT7	ENST00000546666.1 link	n.*119G>T		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250470

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460902

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726756

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152292

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

-0.0051

MutationAssessor

Uncertain

2.8

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.014

Polyphen

0.42

Vest4

0.73

MutPred

0.48

Loss of disorder (P = 0.0662);

MVP

0.78

MPC

0.36

ClinPred

0.90

GERP RS

4.2

Varity_R

0.62

gMVP

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over