Genetic Variant KRTAP4-3:p.Thr97Ile (chr17-41167883-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033187.2(KRTAP4-3):c.290C>T(p.Thr97Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000379 in 1,582,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. T97A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

KRTAP4-3
NM_033187.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00100

Publications

0 publications found

Variant links:

Genes affected

KRTAP4-3 (HGNC:18908): (keratin associated protein 4-3) Involved in aging and hair cycle. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP4-3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14301294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-3	NM_033187.2 link	c.290C>T	p.Thr97Ile	missense_variant	Exon 1 of 1	ENST00000391356.4	NP_149443.1	Q9BYR4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-3	ENST00000391356.4 link	c.290C>T	p.Thr97Ile	missense_variant	Exon 1 of 1	6	NM_033187.2	ENSP00000375151.2		Q9BYR4

Frequencies

GnomAD3 genomes

AF:

0.00000672

AC:

AN:

148878

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000349

AC:

AN:

1433512

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710558

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32434

American (AMR)

AF:

0.00

AC:

AN:

39466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25634

East Asian (EAS)

AF:

0.00

AC:

AN:

38590

South Asian (SAS)

AF:

0.00

AC:

AN:

83076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51786

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4806

European-Non Finnish (NFE)

AF:

0.00000364

AC:

AN:

1098340

Other (OTH)

AF:

0.0000168

AC:

AN:

59380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000672

AC:

AN:

148878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72596

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39462

American (AMR)

AF:

0.00

AC:

AN:

15050

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5092

South Asian (SAS)

AF:

0.00

AC:

AN:

4686

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67484

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 24, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.290C>T (p.T97I) alteration is located in exon 1 (coding exon 1) of the KRTAP4-3 gene. This alteration results from a C to T substitution at nucleotide position 290, causing the threonine (T) at amino acid position 97 to be replaced by an isoleucine (I). 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

Pathogenic

0.64

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.042

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.041

M_CAP

Benign

0.0027

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.4

PhyloP100

-0.0010

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.096

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.022

Polyphen

0.17

Vest4

0.071

MutPred

0.41

Gain of sheet (P = 0.0101);

MVP

0.18

MPC

0.024

ClinPred

0.95

GERP RS

4.8

PromoterAI

0.021

Neutral

(source)

Varity_R

0.27

gMVP

0.071

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr17-41167883-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over