17-41105588-C-G

Variant names:

• chr17-41105588-C-G
• rs981178042
• NM_001146041.1:c.200C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001146041.1(KRTAP4-9):​c.200C>G​(p.Pro67Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,425,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P67L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KRTAP4-9 NM_001146041.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28113097).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146041.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-9	NM_001146041.1	MANE Select	c.200C>G	p.Pro67Arg	missense	Exon 1 of 1	NP_001139513.1	Q9BYQ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-9	ENST00000391415.2	TSL:6 MANE Select	c.200C>G	p.Pro67Arg	missense	Exon 1 of 1	ENSP00000375234.1	Q9BYQ8

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1425812 Hom.: 0 Cov.: 137 AF XY: 0.00 AC XY: 0 AN XY: 709604

African (AFR) AF: 0.00 AC: 0 AN: 30134

American (AMR) AF: 0.00 AC: 0 AN: 39106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25230

East Asian (EAS) AF: 0.00 AC: 0 AN: 29462

South Asian (SAS) AF: 0.00 AC: 0 AN: 84138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102856

Other (OTH) AF: 0.00 AC: 0 AN: 58200

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.086
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	4.2	H
PhyloP100		1.4
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.094
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.85	P
Vest4		0.28
MutPred		0.50		Gain of catalytic residue at P67 (P = 0.0499)
MVP		0.14
MPC		0.19
ClinPred		0.52	D
GERP RS		2.9
PromoterAI		-0.0064	Neutral
Varity_R		0.43
gMVP		0.048
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs981178042; hg19: chr17-39261840;