17-41167770-A-G

Position:

• chr17-41167770-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033187.2(KRTAP4-3):​c.403T>C​(p.Cys135Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRTAP4-3 NM_033187.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.178

Genes affected

KRTAP4-3 (HGNC:18908): (keratin associated protein 4-3) Involved in aging and hair cycle. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.330634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP4-3	NM_033187.2	c.403T>C	p.Cys135Arg	missense_variant	1/1	ENST00000391356.4	NP_149443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP4-3	ENST00000391356.4	c.403T>C	p.Cys135Arg	missense_variant	1/1	6	NM_033187.2	ENSP00000375151.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461250 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726874

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

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

Oct 25, 2024

The c.403T>C (p.C135R) alteration is located in exon 1 (coding exon 1) of the KRTAP4-3 gene. This alteration results from a T to C substitution at nucleotide position 403, causing the cysteine (C) at amino acid position 135 to be replaced by an arginine (R). 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	Uncertain	0.47
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Benign	0.15
Sift	Uncertain	0.027	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.90	P
Vest4		0.12
MutPred		0.75		Gain of solvent accessibility (P = 0.0584);
MVP		0.27
MPC		0.031
ClinPred		0.49	T
GERP RS		4.0
Varity_R		0.68
gMVP		0.11

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: rs760078963; hg19: chr17-39324022;