Genetic Variant NM_031963.3:c.323C>G (chr17-41238374-C-G) – 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_031963.3(KRTAP9-8):c.323C>G(p.Pro108Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000829 in 1,607,406 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00094 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00082 ( 2 hom. )

Consequence

KRTAP9-8
NM_031963.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

Variant links:

Genes affected

KRTAP9-8 (HGNC:17231): (keratin associated protein 9-8) 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]

KRTAP9-8 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=0.09589189).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP9-8	NM_031963.3 link	c.323C>G	p.Pro108Arg	missense_variant	Exon 1 of 1	ENST00000254072.7	NP_114169.2	Q9BYQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP9-8	ENST00000254072.7 link	c.323C>G	p.Pro108Arg	missense_variant	Exon 1 of 1	6	NM_031963.3	ENSP00000254072.6		Q9BYQ0

Frequencies

GnomAD3 genomes

AF:

0.000943

AC:

139

AN:

147424

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000108

Gnomad AMI

AF:

0.00549

Gnomad AMR

AF:

0.00270

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000927

Gnomad OTH

AF:

0.000489

GnomAD3 exomes

AF:

0.000806

AC:

202

AN:

250610

Hom.:

AF XY:

0.000730

AC XY:

AN XY:

135544

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000817

AC:

1193

AN:

1459870

Hom.:

Cov.:

AF XY:

0.000778

AC XY:

565

AN XY:

726376

show subpopulations

Gnomad4 AFR exome

AF:

0.0000949

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.00256

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00129

Gnomad4 NFE exome

AF:

0.000842

Gnomad4 OTH exome

AF:

0.000995

GnomAD4 genome

AF:

0.000942

AC:

139

AN:

147536

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

72142

show subpopulations

Gnomad4 AFR

AF:

0.000108

Gnomad4 AMR

AF:

0.00270

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.000927

Gnomad4 OTH

AF:

0.000484

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.00101

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000702

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.00124

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.323C>G (p.P108R) alteration is located in exon 1 (coding exon 1) of the KRTAP9-8 gene. This alteration results from a C to G substitution at nucleotide position 323, causing the proline (P) at amino acid position 108 to be replaced by an arginine (R). 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

Uncertain

0.34

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

Eigen

Benign

-0.073

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.66

M_CAP

Benign

0.0018

MetaRNN

Benign

0.096

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.1

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-5.5

REVEL

Benign

0.088

Sift

Uncertain

0.022

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.72

MVP

0.088

MPC

0.84

ClinPred

0.23

GERP RS

2.2

Varity_R

0.17

gMVP

0.099

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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