17-41105797-C-G

Position:

• chr17-41105797-C-G

Variant summary

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

The NM_001146041.1(KRTAP4-9):​c.409C>G​(p.Pro137Ala) 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. 13/21 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: KRTAP4-9 NM_001146041.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.276

Genes affected

KRTAP4-9 (HGNC:18910): (keratin associated protein 4-9) 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20295185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP4-9	NM_001146041.1	c.409C>G	p.Pro137Ala	missense_variant	1/1	ENST00000391415.2	NP_001139513.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP4-9	ENST00000391415.2	c.409C>G	p.Pro137Ala	missense_variant	1/1	6	NM_001146041.1	ENSP00000375234.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245964 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134192

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

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

Jan 03, 2024

The c.409C>G (p.P137A) alteration is located in exon 1 (coding exon 1) of the KRTAP4-9 gene. This alteration results from a C to G substitution at nucleotide position 409, causing the proline (P) at amino acid position 137 to be replaced by an alanine (A). 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	0.15
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.81
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Benign	0.23	T
PROVEAN	Pathogenic	-6.7	D;.
REVEL	Benign	0.11
Sift	Benign	0.032	D;.
Sift4G	Uncertain	0.014	D;D
Polyphen		0.26	B;.
Vest4		0.25
MutPred		0.55		Loss of relative solvent accessibility (P = 0.0071);.;
MVP		0.17
MPC		0.17
ClinPred		0.26	T
GERP RS		2.6
Varity_R		0.11
gMVP		0.034

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: rs779680132; hg19: chr17-39262049;