NM_001386841.1:c.413G>T

Variant names:

• chr17-41184442-C-A
• rs112363564
• NM_001386841.1:c.413G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001386841.1(KRTAP4-1):​c.413G>T​(p.Arg138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R138C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRTAP4-1 NM_001386841.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.369
• Publications: 1 publications found

Genes affected

KRTAP4-1 (HGNC:18907): (keratin associated protein 4-1) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the ultrahigh sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16220692).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386841.1. 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
	KRTAP4-1	NM_001386841.1	MANE Select	c.413G>T	p.Arg138Leu	missense	Exon 1 of 1	NP_001373770.1	Q9BYQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-1	ENST00000398472.2	TSL:6 MANE Select	c.413G>T	p.Arg138Leu	missense	Exon 1 of 1	ENSP00000381489.1	Q9BYQ7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000817 AC: 2 AN: 244672 AF XY: 0.00000756

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451482 Hom.: 0 Cov.: 77 AF XY: 0.00000139 AC XY: 1 AN XY: 720248

African (AFR) AF: 0.00 AC: 0 AN: 33284

American (AMR) AF: 0.0000225 AC: 1 AN: 44468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.00 AC: 0 AN: 85062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105040

Other (OTH) AF: 0.00 AC: 0 AN: 59908

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 3

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.10	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.91	T
PhyloP100		-0.37
PrimateAI	Benign	0.20	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.064
Sift	Benign	0.067	T
Sift4G	Uncertain	0.018	D
Polyphen		0.81	P
Vest4		0.22
MutPred		0.51		Loss of sheet (P = 0.0228)
MVP		0.14
MPC		0.20
ClinPred		0.49	T
GERP RS		1.9
PromoterAI		0.010	Neutral
Varity_R		0.17
gMVP		0.078

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

Other links and lift over

dbSNP: rs112363564; hg19: chr17-39340694;