Genetic Variant KRTAP4-11:p.Arg101Cys (chr17-41118015-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_033059.4(KRTAP4-11):c.301C>T(p.Arg101Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,474,290 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R101H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00012 ( 4 hom. )

Consequence

KRTAP4-11
NM_033059.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -8.00

Variant links:

Genes affected

KRTAP4-11 (HGNC:18911): (keratin associated protein 4-11) 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, Mar 2009]

KRTAP4-11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029323846).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-11	NM_033059.4 link	c.301C>T	p.Arg101Cys	missense_variant	Exon 1 of 1	ENST00000391413.4	NP_149048.2	Q9BYQ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-11	ENST00000391413.4 link	c.301C>T	p.Arg101Cys	missense_variant	Exon 1 of 1	6	NM_033059.4	ENSP00000375232.2		Q9BYQ6

Frequencies

GnomAD3 genomes

AF:

0.000186

AC:

AN:

145108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000546

Gnomad ASJ

AF:

0.00261

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000211

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000933

AC:

AN:

246470

Hom.:

AF XY:

0.0000894

AC XY:

AN XY:

134292

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000177

Gnomad ASJ exome

AF:

0.000808

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000625

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

162

AN:

1329088

Hom.:

Cov.:

198

AF XY:

0.000144

AC XY:

AN XY:

654734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000343

Gnomad4 ASJ exome

AF:

0.00254

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000629

Gnomad4 OTH exome

AF:

0.000243

GnomAD4 genome

AF:

0.000186

AC:

AN:

145202

Hom.:

Cov.:

AF XY:

0.000240

AC XY:

AN XY:

70908

show subpopulations

Gnomad4 AFR

AF:

0.0000274

Gnomad4 AMR

AF:

0.000546

Gnomad4 ASJ

AF:

0.00261

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000212

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000291

Hom.:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.301C>T (p.R101C) alteration is located in exon 1 (coding exon 1) of the KRTAP4-11 gene. This alteration results from a C to T substitution at nucleotide position 301, causing the arginine (R) at amino acid position 101 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.10

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.055

LIST_S2

Benign

0.45

M_CAP

Benign

0.0051

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.1

PrimateAI

Benign

0.19

PROVEAN

Pathogenic

-5.8

REVEL

Benign

0.088

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

0.14

Vest4

0.11

MutPred

0.54

Loss of sheet (P = 0.0817);

MVP

0.072

MPC

0.0083

ClinPred

0.98

GERP RS

-7.9

Varity_R

0.29

gMVP

0.076

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over