Genetic Variant KRTAP9-2:p.Thr89Ile (chr17-41226920-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031961.3(KRTAP9-2):c.266C>T(p.Thr89Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 0.00038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRTAP9-2
NM_031961.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.878

Variant links:

Genes affected

KRTAP9-2 (HGNC:16926): (keratin associated protein 9-2) 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, Jul 2008]

KRTAP9-2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.088713825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP9-2	NM_031961.3 link	c.266C>T	p.Thr89Ile	missense_variant	Exon 1 of 1	ENST00000377721.3	NP_114167.2	Q9BYQ4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP9-2	ENST00000377721.3 link	c.266C>T	p.Thr89Ile	missense_variant	Exon 1 of 1	6	NM_031961.3	ENSP00000366950.3		Q9BYQ4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

146210

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000744

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000274

Gnomad ASJ

AF:

0.000297

Gnomad EAS

AF:

0.000400

Gnomad SAS

AF:

0.000439

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000610

Gnomad OTH

AF:

0.00101

GnomAD3 exomes

AF:

0.0000678

AC:

AN:

250676

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135664

show subpopulations

Gnomad AFR exome

AF:

0.0000627

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:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000123

AC:

AN:

1461242

Hom.:

Cov.:

208

AF XY:

0.00000825

AC XY:

AN XY:

726932

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000376

AC:

AN:

146312

Hom.:

Cov.:

AF XY:

0.000534

AC XY:

AN XY:

71104

show subpopulations

Gnomad4 AFR

AF:

0.0000742

Gnomad4 AMR

AF:

0.000274

Gnomad4 ASJ

AF:

0.000297

Gnomad4 EAS

AF:

0.000602

Gnomad4 SAS

AF:

0.000440

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000611

Gnomad4 OTH

AF:

0.000997

Alfa

AF:

0.00674

Hom.:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.266C>T (p.T89I) alteration is located in exon 1 (coding exon 1) of the KRTAP9-2 gene. This alteration results from a C to T substitution at nucleotide position 266, causing the threonine (T) at amino acid position 89 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

Benign

0.11

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

3.6

DANN

Benign

0.81

DEOGEN2

Benign

0.031

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.055

M_CAP

Benign

0.0033

MetaRNN

Benign

0.089

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.029

Sift

Benign

0.085

Sift4G

Benign

0.066

Polyphen

0.48

Vest4

0.063

MutPred

0.42

Loss of relative solvent accessibility (P = 0.0071);

MVP

0.10

MPC

1.2

ClinPred

0.14

GERP RS

1.3

Varity_R

0.14

gMVP

0.074

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

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