NM_033191.3:c.104C>A

Variant names:

• chr17-41249824-C-A
• rs746726849
• NM_033191.3:c.104C>A

Variant summary

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

The NM_033191.3(KRTAP9-4):​c.104C>A​(p.Thr35Lys) 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. 15/22 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. T35I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP9-4 NM_033191.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.187
• Publications: 0 publications found

Genes affected

KRTAP9-4 (HGNC:18902): (keratin associated protein 9-4) 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]

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=0.046464533).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033191.3. 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
	KRTAP9-4	NM_033191.3	MANE Select	c.104C>A	p.Thr35Lys	missense	Exon 1 of 1	NP_149461.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP9-4	ENST00000334109.3	TSL:6 MANE Select	c.104C>A	p.Thr35Lys	missense	Exon 1 of 1	ENSP00000334922.2	Q9BYQ2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250306 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000359 AC: 5 AN: 1390836 Hom.: 0 Cov.: 149 AF XY: 0.00000432 AC XY: 3 AN XY: 693790

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

African (AFR) AF: 0.00 AC: 0 AN: 32036

American (AMR) AF: 0.00 AC: 0 AN: 41026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24876

East Asian (EAS) AF: 0.00 AC: 0 AN: 38062

South Asian (SAS) AF: 0.0000591 AC: 5 AN: 84584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4818

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1054906

Other (OTH) AF: 0.00 AC: 0 AN: 57334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0131613), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.011	N
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.19
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.031
Sift	Benign	0.46	T
Sift4G	Uncertain	0.022	D
Polyphen		0.0020	B
Vest4		0.20
MutPred		0.48		Gain of methylation at T35 (P = 0.0023)
MVP		0.16
MPC		0.11
ClinPred		0.048	T
GERP RS		-1.5
PromoterAI		-0.012	Neutral
Varity_R		0.082
gMVP		0.094

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

Other links and lift over

dbSNP: rs746726849; hg19: chr17-39406076;