17-41255614-A-T

Variant names:

• chr17-41255614-A-T
• rs1489136034
• NM_030975.2:c.229A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_030975.2(KRTAP9-9):​c.229A>T​(p.Ser77Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S77G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: KRTAP9-9 NM_030975.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.74
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060512245).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030975.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP9-9	NM_030975.2	MANE Select	c.229A>T	p.Ser77Cys	missense	Exon 1 of 1	NP_112237.2	Q9BYP9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP9-9	ENST00000394008.1	TSL:6 MANE Select	c.229A>T	p.Ser77Cys	missense	Exon 1 of 1	ENSP00000377576.1	Q9BYP9-3

Frequencies

GnomAD3 genomes AF: 0.0000154 AC: 2 AN: 129766 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000293

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: 0.0000166

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000154 AC: 2 AN: 129766 Hom.: 0 Cov.: 31 AF XY: 0.0000158 AC XY: 1 AN XY: 63338

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000293 AC: 1 AN: 34120

American (AMR) AF: 0.00 AC: 0 AN: 12924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3188

East Asian (EAS) AF: 0.00 AC: 0 AN: 4282

South Asian (SAS) AF: 0.00 AC: 0 AN: 4090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 156

European-Non Finnish (NFE) AF: 0.0000166 AC: 1 AN: 60190

Other (OTH) AF: 0.00 AC: 0 AN: 1744

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.7
DANN	Benign	0.89
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0062	N
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.92	T
PhyloP100		-2.7
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.027
Sift	Benign	0.039	D
Sift4G	Uncertain	0.050	T
Vest4		0.13
MutPred		0.35		Loss of glycosylation at S77 (P = 0.0725)
MVP		0.030
MPC		0.034
ClinPred		0.089	T
GERP RS		-4.3
PromoterAI		0.00050	Neutral
gMVP		0.042

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

Other links and lift over

dbSNP: rs1489136034; hg19: chr17-39411866;