Genetic Variant KRTAP4-8:p.Arg126Leu (chr17-41097708-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_031960.3(KRTAP4-8):c.377G>T(p.Arg126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 708,280 control chromosomes in the GnomAD database, including 3 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 (★).

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000046 ( 3 hom. )

Consequence

KRTAP4-8
NM_031960.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.56

Variant links:

Genes affected

KRTAP4-8 (HGNC:17230): (keratin associated protein 4-8) Involved in aging and hair cycle. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP4-8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09813452).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-8	NM_031960.3 link	c.377G>T	p.Arg126Leu	missense_variant	Exon 1 of 1	ENST00000333822.5	NP_114166.1	Q9BYQ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-8	ENST00000333822.5 link	c.377G>T	p.Arg126Leu	missense_variant	Exon 1 of 1	6	NM_031960.3	ENSP00000328444.4		Q9BYQ9

Frequencies

GnomAD3 genomes

AF:

0.0000161

AC:

AN:

124130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000342

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000298

AC:

AN:

100516

Hom.:

AF XY:

0.00

AC XY:

AN XY:

55042

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000133

Gnomad NFE exome

AF:

0.0000526

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000462

AC:

AN:

584150

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

297768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000610

Gnomad4 NFE exome

AF:

0.0000570

Gnomad4 OTH exome

AF:

0.0000690

GnomAD4 genome

AF:

0.0000161

AC:

AN:

124130

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

60568

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000342

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.377G>T (p.R126L) alteration is located in exon 1 (coding exon 1) of the KRTAP4-8 gene. This alteration results from a G to T substitution at nucleotide position 377, causing the arginine (R) at amino acid position 126 to be replaced by a leucine (L). 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

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.072

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.13

T;T

M_CAP

Benign

0.0021

MetaRNN

Benign

0.098

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Pathogenic

4.0

H;.

PrimateAI

Benign

0.18

PROVEAN

Pathogenic

-4.9

D;.

REVEL

Benign

0.024

Sift

Uncertain

0.024

D;.

Sift4G

Uncertain

0.057

T;T

Polyphen

0.065

B;.

Vest4

0.14

MutPred

0.51

Loss of phosphorylation at S128 (P = 0.0545);.;

MVP

0.040

MPC

0.11

ClinPred

0.22

GERP RS

-2.0

Varity_R

0.16

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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