Genetic Variant NM_000421.5:c.1460A>T (chr17-40819075-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000421.5(KRT10):c.1460A>T(p.His487Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,215,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. H487R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000094 ( 0 hom., cov: 26)

Exomes 𝑓: 9.0e-7 ( 0 hom. )

Consequence

KRT10
NM_000421.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.73

Publications

5 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.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0790396).

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.1460A>T	p.His487Leu	missense	Exon 7 of 8	NP_000412.4
KRT10	NM_001379366.1		c.1460A>T	p.His487Leu	missense	Exon 7 of 8	NP_001366295.1	A0A1B0GVI3
KRT10-AS1	NR_160886.1		n.-110T>A		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT10	ENST00000269576.6	TSL:1 MANE Select	c.1460A>T	p.His487Leu	missense	Exon 7 of 8	ENSP00000269576.5	P13645
KRT10	ENST00000635956.2	TSL:2	c.1460A>T	p.His487Leu	missense	Exon 7 of 8	ENSP00000490524.2	A0A1B0GVI3
KRT10-AS1	ENST00000436612.7	TSL:2	n.5T>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.00000937

AC:

AN:

106736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000312

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

GnomAD4 exome

AF:

9.02e-7

AC:

AN:

1108474

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

546748

show subpopulations

African (AFR)

AF:

0.0000410

AC:

AN:

24368

American (AMR)

AF:

0.00

AC:

AN:

19474

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18956

East Asian (EAS)

AF:

0.00

AC:

AN:

21860

South Asian (SAS)

AF:

0.00

AC:

AN:

61964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3498

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

884894

Other (OTH)

AF:

0.00

AC:

AN:

45870

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000937

AC:

AN:

106736

Hom.:

Cov.:

AF XY:

0.0000192

AC XY:

AN XY:

52034

show subpopulations

African (AFR)

AF:

0.0000312

AC:

AN:

32008

American (AMR)

AF:

0.00

AC:

AN:

11118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2330

East Asian (EAS)

AF:

0.00

AC:

AN:

2930

South Asian (SAS)

AF:

0.00

AC:

AN:

2928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

162

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

47250

Other (OTH)

AF:

0.00

AC:

AN:

1424

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Benign

2.3

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.10

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.17

M_CAP

Benign

0.056

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.64

MutationAssessor

Benign

-0.55

PhyloP100

-1.7

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.35

REVEL

Benign

0.20

Sift

Uncertain

0.0070

Sift4G

Benign

0.64

Polyphen

0.0010

Vest4

0.20

MutPred

0.39

Gain of stability (P = 0.25)

MVP

0.62

MPC

0.52

ClinPred

0.26

GERP RS

1.1

Varity_R

0.34

gMVP

0.47

Mutation Taster

=98/2

polymorphism

(source)

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

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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