17-41255468-G-A

Position:

• chr17-41255468-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_030975.2(KRTAP9-9):​c.83G>A​(p.Ser28Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,441,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KRTAP9-9 NM_030975.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

KRTAP9-9 (HGNC:16773): (keratin associated protein 9-9) 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. Alternative haplotypes of this gene are represented in the GRCh38 reference genome assembly. [provided by RefSeq, Dec 2015]

ACMG classification

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=0.05937597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP9-9	NM_030975.2	c.83G>A	p.Ser28Asn	missense_variant	1/1		NP_112237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP9-9	ENST00000394008.1	c.83G>A	p.Ser28Asn	missense_variant	1/1	6		ENSP00000377576.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1441024 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 716664

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.09e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.83G>A (p.S28N) alteration is located in exon 1 (coding exon 1) of the KRTAP9-9 gene. This alteration results from a G to A substitution at nucleotide position 83, causing the serine (S) at amino acid position 28 to be replaced by an asparagine (N). 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
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.90
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.030	N
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.86	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.055
Sift	Benign	0.14	T
Sift4G	Uncertain	0.042	D
Vest4		0.15
MVP		0.14
MPC		0.034
ClinPred		0.17	T
GERP RS		2.0
gMVP		0.023

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

Other links and lift over

dbSNP: rs1176825985; hg19: chr17-39411720;