17-41059827-C-A

Position:

• chr17-41059827-C-A

Variant summary

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

The NM_001165252.2(KRTAP2-3):​c.224G>T​(p.Arg75Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRTAP2-3 NM_001165252.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.847

Genes affected

KRTAP2-3 (HGNC:18906): (keratin associated protein 2-3) 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=0.2898363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP2-3	NM_001165252.2	c.224G>T	p.Arg75Leu	missense_variant	1/1	ENST00000391418.3	NP_001158724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP2-3	ENST00000391418.3	c.224G>T	p.Arg75Leu	missense_variant	1/1	6	NM_001165252.2	ENSP00000375237.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

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

May 08, 2024

The c.224G>T (p.R75L) alteration is located in exon 1 (coding exon 1) of the KRTAP2-3 gene. This alteration results from a G to T substitution at nucleotide position 224, causing the arginine (R) at amino acid position 75 to be replaced by a leucine (L). 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
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.048
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Vest4		0.38
MutPred		0.67		Loss of phosphorylation at T78 (P = 0.0619);
MVP		0.30
MPC		2.5
ClinPred		0.98	D
GERP RS		2.3
Varity_R		0.19
gMVP		0.13

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

LitVar

Other links and lift over

dbSNP: rs1173910172; hg19: chr17-39216079;