Genetic Variant KRTAP5-7:p.Val159Met (chr11-71527775-G-A) – 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_001012503.2(KRTAP5-7):c.475G>A(p.Val159Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,564,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000058 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

KRTAP5-7
NM_001012503.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.921

Variant links:

Genes affected

KRTAP5-7 (HGNC:23602): (keratin associated protein 5-7) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP5-7 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=0.06691536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP5-7	NM_001012503.2 link	c.475G>A	p.Val159Met	missense_variant	Exon 1 of 1	ENST00000398536.6	NP_001012521.1	Q6L8G8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP5-7	ENST00000398536.6 link	c.475G>A	p.Val159Met	missense_variant	Exon 1 of 1	6	NM_001012503.2	ENSP00000417330.2		Q6L8G8

Frequencies

GnomAD3 genomes

AF:

0.0000577

AC:

AN:

138692

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000279

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:

0.000108

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000689

AC:

AN:

246776

Hom.:

AF XY:

0.0000527

AC XY:

AN XY:

132878

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000343

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000447

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000210

AC:

AN:

1425802

Hom.:

Cov.:

AF XY:

0.0000169

AC XY:

AN XY:

709058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000638

Gnomad4 AMR exome

AF:

0.000138

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000298

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000137

Gnomad4 OTH exome

AF:

0.0000518

GnomAD4 genome

AF:

0.0000577

AC:

AN:

138692

Hom.:

Cov.:

AF XY:

0.0000595

AC XY:

AN XY:

67250

show subpopulations

Gnomad4 AFR

AF:

0.0000279

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:

0.000108

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000905

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.475G>A (p.V159M) alteration is located in exon 1 (coding exon 1) of the KRTAP5-7 gene. This alteration results from a G to A substitution at nucleotide position 475, causing the valine (V) at amino acid position 159 to be replaced by a methionine (M). 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

0.16

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.068

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.026

M_CAP

Benign

0.00081

MetaRNN

Benign

0.067

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PROVEAN

Benign

-0.96

REVEL

Benign

0.054

Sift

Uncertain

0.011

Sift4G

Benign

0.079

Polyphen

0.82

Vest4

0.18

MutPred

0.21

Loss of ubiquitination at K164 (P = 0.1381);

MVP

0.043

MPC

0.011

ClinPred

0.10

GERP RS

-3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.052

gMVP

0.011

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