Genetic Variant KRTAP4-6:p.Arg62His (chr17-41140303-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_030976.2(KRTAP4-6):c.185G>A(p.Arg62His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,603,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

KRTAP4-6
NM_030976.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.895

Variant links:

Genes affected

KRTAP4-6 (HGNC:18909): (keratin associated protein 4-6) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP4-6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05200818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-6	NM_030976.2 link	c.185G>A	p.Arg62His	missense_variant	Exon 1 of 1	ENST00000345847.5	NP_112238.1	Q9BYQ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-6	ENST00000345847.5 link	c.185G>A	p.Arg62His	missense_variant	Exon 1 of 1	6	NM_030976.2	ENSP00000328270.5		Q9BYQ5

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150580

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000723

AC:

AN:

248960

Hom.:

AF XY:

0.0000739

AC XY:

AN XY:

135242

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000382

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000533

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000310

AC:

AN:

1452354

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

722992

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000229

Gnomad4 ASJ exome

AF:

0.0000386

Gnomad4 EAS exome

AF:

0.000253

Gnomad4 SAS exome

AF:

0.0000815

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000207

Gnomad4 OTH exome

AF:

0.0000504

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150686

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73604

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:

0.0000295

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000165

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

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.185G>A (p.R62H) alteration is located in exon 1 (coding exon 1) of the KRTAP4-6 gene. This alteration results from a G to A substitution at nucleotide position 185, causing the arginine (R) at amino acid position 62 to be replaced by a histidine (H). 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

-0.56

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.089

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0076

LIST_S2

Benign

0.29

M_CAP

Benign

0.00089

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.17

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.018

Sift

Benign

0.081

Sift4G

Benign

0.12

Vest4

0.051

MutPred

0.40

Gain of glycosylation at S64 (P = 0.1048);

MVP

0.030

MPC

0.065

ClinPred

0.064

GERP RS

-4.9

Varity_R

0.038

gMVP

0.10

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