17-41140342-T-C

Position:

• chr17-41140342-T-C

Variant summary

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

The NM_030976.2(KRTAP4-6):​c.146A>G​(p.Gln49Arg) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRTAP4-6 NM_030976.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.93

Genes affected

KRTAP4-6 (HGNC:18909): (keratin associated protein 4-6) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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=0.07418087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP4-6	NM_030976.2	c.146A>G	p.Gln49Arg	missense_variant	1/1	ENST00000345847.5	NP_112238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP4-6	ENST00000345847.5	c.146A>G	p.Gln49Arg	missense_variant	1/1	6	NM_030976.2	ENSP00000328270.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

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

Mar 27, 2023

The c.146A>G (p.Q49R) alteration is located in exon 1 (coding exon 1) of the KRTAP4-6 gene. This alteration results from a A to G substitution at nucleotide position 146, causing the glutamine (Q) at amino acid position 49 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	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.3
DANN	Benign	0.38
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.043	T
M_CAP	Benign	0.00083	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.029
Sift	Benign	0.54	T
Sift4G	Benign	0.16	T
Vest4		0.059
MutPred		0.35		Gain of phosphorylation at S44 (P = 0.185);
MVP		0.030
MPC		0.058
ClinPred		0.091	T
GERP RS		-6.3
Varity_R		0.061
gMVP		0.088

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: chr17-39296594; COSMIC: COSV61981522;