17-41249887-G-T

Variant names:

• chr17-41249887-G-T
• rs758883454
• NM_033191.3:c.167G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033191.3(KRTAP9-4):​c.167G>T​(p.Cys56Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C56S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP9-4 NM_033191.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.167G>T	p.Cys56Phe	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.167G>T	p.Cys56Phe	missense	Exon 1 of 1	ENSP00000334922.2	Q9BYQ2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251366 AF XY: 0.00000736

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: 7.19e-7 AC: 1 AN: 1390970 Hom.: 0 Cov.: 188 AF XY: 0.00000144 AC XY: 1 AN XY: 693396

⚠️ 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: 32060

American (AMR) AF: 0.00 AC: 0 AN: 40586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24862

East Asian (EAS) AF: 0.00 AC: 0 AN: 37958

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5448

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1055778

Other (OTH) AF: 0.00 AC: 0 AN: 57406

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.0015	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		1.6
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-9.9	D
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.52		Gain of relative solvent accessibility (P = 0.09)
MVP		0.46
MPC		0.14
ClinPred		0.62	D
GERP RS		2.6
PromoterAI		-0.0086	Neutral
Varity_R		0.81
gMVP		0.12

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: rs758883454; hg19: chr17-39406139;