Genetic Variant KRT10:p.His487ArgfsTer97 (chr17-40819075-T-TAGCCGCCGCC) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 8P and 8B. PVS1BA1

The NM_000421.5(KRT10):c.1459_1460insGGCGGCGGCT(p.His487ArgfsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 106,746 control chromosomes in the GnomAD database, including 142 homozygotes. Variant has been reported in ClinVar as Uncertain significance (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.029 ( 142 hom., cov: 24)

Exomes 𝑓: 0.0032 ( 83 hom. )

Failed GnomAD Quality Control

Consequence

KRT10
NM_000421.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:2

Conservation

PhyloP100: -0.352

Publications

3 publications found

Variant links:

Genes affected

KRT10 (HGNC:6413): (keratin 10) This gene encodes a member of the type I (acidic) cytokeratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. Mutations in this gene are associated with epidermolytic hyperkeratosis. This gene is located within a cluster of keratin family members on chromosome 17q21. [provided by RefSeq, Jul 2008]

KRT10 links:

KRT10-AS1 (HGNC:28305): (KRT10 antisense RNA 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

KRT10-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0885 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000421.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT10	NM_000421.5	MANE Select	c.1459_1460insGGCGGCGGCT	p.His487ArgfsTer97	frameshift	Exon 7 of 8	NP_000412.4
KRT10	NM_001379366.1		c.1459_1460insGGCGGCGGCT	p.His487ArgfsTer97	frameshift	Exon 7 of 8	NP_001366295.1	A0A1B0GVI3
KRT10-AS1	NR_160886.1		n.-110_-109insAGCCGCCGCC		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT10	ENST00000269576.6	TSL:1 MANE Select	c.1459_1460insGGCGGCGGCT	p.His487ArgfsTer97	frameshift	Exon 7 of 8	ENSP00000269576.5	P13645
KRT10	ENST00000635956.2	TSL:2	c.1459_1460insGGCGGCGGCT	p.His487ArgfsTer97	frameshift	Exon 7 of 8	ENSP00000490524.2	A0A1B0GVI3
KRT10-AS1	ENST00000436612.7	TSL:2	n.5_6insAGCCGCCGCC		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0294

AC:

3131

AN:

106670

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0913

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00783

Gnomad ASJ

AF:

0.00815

Gnomad EAS

AF:

0.00580

Gnomad SAS

AF:

0.00102

Gnomad FIN

AF:

0.000165

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000974

Gnomad OTH

AF:

0.0288

GnomAD2 exomes

AF:

0.00217

AC:

134

AN:

61774

AF XY:

0.00190

show subpopulations

Gnomad AFR exome

AF:

0.0624

Gnomad AMR exome

AF:

0.00210

Gnomad ASJ exome

AF:

0.00465

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000823

Gnomad OTH exome

AF:

0.00118

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00315

AC:

3492

AN:

1108360

Hom.:

Cov.:

109

AF XY:

0.00292

AC XY:

1595

AN XY:

546698

show subpopulations

African (AFR)

AF:

0.0821

AC:

1995

AN:

24304

American (AMR)

AF:

0.00426

AC:

AN:

19472

Ashkenazi Jewish (ASJ)

AF:

0.00617

AC:

117

AN:

18954

East Asian (EAS)

AF:

0.000640

AC:

AN:

21860

South Asian (SAS)

AF:

0.000807

AC:

AN:

61960

European-Finnish (FIN)

AF:

0.000290

AC:

AN:

27590

Middle Eastern (MID)

AF:

0.00286

AC:

AN:

3498

European-Non Finnish (NFE)

AF:

0.00104

AC:

920

AN:

884864

Other (OTH)

AF:

0.00643

AC:

295

AN:

45858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

172

344

516

688

860

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0294

AC:

3138

AN:

106746

Hom.:

142

Cov.:

AF XY:

0.0281

AC XY:

1464

AN XY:

52080

show subpopulations

African (AFR)

AF:

0.0913

AC:

2926

AN:

32046

American (AMR)

AF:

0.00782

AC:

AN:

11122

Ashkenazi Jewish (ASJ)

AF:

0.00815

AC:

AN:

2330

East Asian (EAS)

AF:

0.00514

AC:

AN:

2916

South Asian (SAS)

AF:

0.00103

AC:

AN:

2910

European-Finnish (FIN)

AF:

0.000165

AC:

AN:

6070

Middle Eastern (MID)

AF:

0.00

AC:

AN:

150

European-Non Finnish (NFE)

AF:

0.000974

AC:

AN:

47244

Other (OTH)

AF:

0.0284

AC:

AN:

1444

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

127

253

380

506

633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.35

Mutation Taster

=144/56

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over