17-41249820-A-T

Position:

• chr17-41249820-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033191.3(KRTAP9-4):​c.100A>T​(p.Ser34Cys) 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRTAP9-4 NM_033191.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.646

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.104785234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP9-4	NM_033191.3	c.100A>T	p.Ser34Cys	missense_variant	1/1	ENST00000334109.3	NP_149461.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP9-4	ENST00000334109.3	c.100A>T	p.Ser34Cys	missense_variant	1/1	6	NM_033191.3	ENSP00000334922.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 148

GnomAD4 genome Cov.: 31

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

Aug 27, 2024

The c.100A>T (p.S34C) alteration is located in exon 1 (coding exon 1) of the KRTAP9-4 gene. This alteration results from a A to T substitution at nucleotide position 100, causing the serine (S) at amino acid position 34 to be replaced by a cysteine (C). 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	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	9.6
DANN	Benign	0.65
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.044	N
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.035
Sift	Benign	0.14	T
Sift4G	Benign	0.084	T
Polyphen		0.80	P
Vest4		0.16
MutPred		0.34		Loss of relative solvent accessibility (P = 0.0071);
MVP		0.36
MPC		0.086
ClinPred		0.13	T
GERP RS		1.4
Varity_R		0.077
gMVP		0.044

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-39406072;