Genetic Variant KRT25:p.Lys363Lys (chr17-40750466-C-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_181534.4(KRT25):c.1089G>A(p.Lys363Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,614,038 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 7 hom., cov: 32)

Exomes 𝑓: 0.011 ( 107 hom. )

Consequence

KRT25
NM_181534.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.37

Publications

4 publications found

Variant links:

Genes affected

KRT25 (HGNC:30839): (keratin 25) This gene encodes a member of the type I (acidic) keratin 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. The type I keratin genes are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jul 2009]

KRT25 Gene-Disease associations (from GenCC):

wooly hair, autosomal recessive 3
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
isolated familial wooly hair disorder
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRT25 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 17-40750466-C-T is Benign according to our data. Variant chr17-40750466-C-T is described in ClinVar as Benign. ClinVar VariationId is 708240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.37 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181534.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT25	NM_181534.4	MANE Select	c.1089G>A	p.Lys363Lys	synonymous	Exon 6 of 8	NP_853512.1	Q7Z3Z0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT25	ENST00000312150.5	TSL:1 MANE Select	c.1089G>A	p.Lys363Lys	synonymous	Exon 6 of 8	ENSP00000310573.4	Q7Z3Z0

Frequencies

GnomAD3 genomes

AF:

0.00851

AC:

1295

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00563

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.0104

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00965

AC:

2425

AN:

251286

AF XY:

0.0102

show subpopulations

Gnomad AFR exome

AF:

0.00271

Gnomad AMR exome

AF:

0.00610

Gnomad ASJ exome

AF:

0.0176

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.0131

Gnomad OTH exome

AF:

0.00946

GnomAD4 exome

AF:

0.0114

AC:

16598

AN:

1461758

Hom.:

107

Cov.:

AF XY:

0.0113

AC XY:

8240

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00176

AC:

AN:

33472

American (AMR)

AF:

0.00602

AC:

269

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0178

AC:

464

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00729

AC:

629

AN:

86252

European-Finnish (FIN)

AF:

0.0102

AC:

546

AN:

53420

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0125

AC:

13929

AN:

1111912

Other (OTH)

AF:

0.0108

AC:

651

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

1039

2078

3117

4156

5195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

508

1016

1524

2032

2540

<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:

0.00850

AC:

1294

AN:

152280

Hom.:

Cov.:

AF XY:

0.00803

AC XY:

598

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

41558

American (AMR)

AF:

0.00562

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00601

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0104

AC:

110

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0131

AC:

892

AN:

68020

Other (OTH)

AF:

0.0128

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0122

Hom.:

Bravo

AF:

0.00822

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0141

EpiControl

AF:

0.0135

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

2.4

(source)

DANN

Benign

0.49

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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