Genetic Variant KRTAP4-4:p.Gln89His (chr17-41160425-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032524.2(KRTAP4-4):c.267A>C(p.Gln89His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q89Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 23)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRTAP4-4
NM_032524.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.762

Publications

2 publications found

Variant links:

Genes affected

KRTAP4-4 (HGNC:16928): (keratin associated protein 4-4) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the ultrahigh sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

KRTAP4-4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.050222576).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032524.2. 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
	KRTAP4-4	NM_032524.2	MANE Select	c.267A>C	p.Gln89His	missense	Exon 1 of 1	NP_115913.1	Q9BYR3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-4	ENST00000390661.5	TSL:6 MANE Select	c.267A>C	p.Gln89His	missense	Exon 1 of 1	ENSP00000375076.3	Q9BYR3

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

153

AN:

69096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00273

Gnomad AMI

AF:

0.00571

Gnomad AMR

AF:

0.00159

Gnomad ASJ

AF:

0.00281

Gnomad EAS

AF:

0.00511

Gnomad SAS

AF:

0.00203

Gnomad FIN

AF:

0.00313

Gnomad MID

AF:

0.0303

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.00202

GnomAD2 exomes

AF:

0.0000129

AC:

AN:

232066

AF XY:

0.0000237

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000128

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000935

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000683

AC:

AN:

1317734

Hom.:

Cov.:

AF XY:

0.00000916

AC XY:

AN XY:

655290

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000712

AC:

AN:

28072

American (AMR)

AF:

0.0000280

AC:

AN:

35666

Ashkenazi Jewish (ASJ)

AF:

0.0000479

AC:

AN:

20878

East Asian (EAS)

AF:

0.000107

AC:

AN:

27910

South Asian (SAS)

AF:

0.00

AC:

AN:

77666

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4982

European-Non Finnish (NFE)

AF:

9.75e-7

AC:

AN:

1025530

Other (OTH)

AF:

0.0000196

AC:

AN:

50992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00223

AC:

154

AN:

69170

Hom.:

Cov.:

AF XY:

0.00201

AC XY:

AN XY:

33758

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00277

AC:

AN:

17666

American (AMR)

AF:

0.00159

AC:

AN:

6932

Ashkenazi Jewish (ASJ)

AF:

0.00281

AC:

AN:

1780

East Asian (EAS)

AF:

0.00512

AC:

AN:

2148

South Asian (SAS)

AF:

0.00203

AC:

AN:

1968

European-Finnish (FIN)

AF:

0.00313

AC:

AN:

3832

Middle Eastern (MID)

AF:

0.0294

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00168

AC:

AN:

33422

Other (OTH)

AF:

0.00199

AC:

AN:

1004

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

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

0.20

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.5

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.0030

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.072

M_CAP

Benign

0.0021

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.3

PhyloP100

-0.76

PrimateAI

Benign

0.18

PROVEAN

Benign

-1.5

REVEL

Benign

0.010

Sift

Uncertain

0.016

Sift4G

Benign

0.093

Polyphen

0.0020

Vest4

0.085

MutPred

0.39

Loss of sheet (P = 0.1907)

MVP

0.040

MPC

0.0084

ClinPred

0.046

GERP RS

-2.2

PromoterAI

-0.0064

Neutral

(source)

Varity_R

0.079

gMVP

0.056

Mutation Taster

=97/3

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

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