Genetic Variant KRTAP4-1:p.Arg138His (chr17-41184442-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001386841.1(KRTAP4-1):c.413G>A(p.Arg138His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,603,788 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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. R138C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0059 ( 13 hom., cov: 34)

Exomes 𝑓: 0.00057 ( 7 hom. )

Consequence

KRTAP4-1
NM_001386841.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.369

Variant links:

Genes affected

KRTAP4-1 (HGNC:18907): (keratin associated protein 4-1) 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]

KRTAP4-1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049245656).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0059 (898/152306) while in subpopulation AFR AF= 0.0206 (858/41554). AF 95% confidence interval is 0.0195. There are 13 homozygotes in gnomad4. There are 426 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-1	NM_001386841.1 link	c.413G>A	p.Arg138His	missense_variant	Exon 1 of 1	ENST00000398472.2	NP_001373770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-1	ENST00000398472.2 link	c.413G>A	p.Arg138His	missense_variant	Exon 1 of 1	6	NM_001386841.1	ENSP00000381489.1		Q9BYQ7

Frequencies

GnomAD3 genomes

AF:

0.00586

AC:

892

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0206

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

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:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00141

AC:

346

AN:

244672

Hom.:

AF XY:

0.00113

AC XY:

149

AN XY:

132342

show subpopulations

Gnomad AFR exome

AF:

0.0202

Gnomad AMR exome

AF:

0.000669

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000548

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000722

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.000573

AC:

832

AN:

1451482

Hom.:

Cov.:

AF XY:

0.000473

AC XY:

341

AN XY:

720248

show subpopulations

Gnomad4 AFR exome

AF:

0.0199

Gnomad4 AMR exome

AF:

0.000810

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000470

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000380

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.00590

AC:

898

AN:

152306

Hom.:

Cov.:

AF XY:

0.00572

AC XY:

426

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0206

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.000846

Hom.:

Bravo

AF:

0.00667

ESP6500AA

AF:

0.0185

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00181

AC:

219

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.78

CADD

Benign

8.2

DANN

Benign

0.90

DEOGEN2

Benign

0.079

T;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.13

T;T

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.93

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-3.1

.;D

REVEL

Benign

0.028

Sift

Uncertain

0.024

.;D

Sift4G

Benign

0.066

T;T

Polyphen

0.019

.;B

Vest4

0.18

MVP

0.030

MPC

0.20

ClinPred

0.016

GERP RS

1.9

Varity_R

0.059

gMVP

0.055

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