17-41184442-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001386841.1(KRTAP4-1):​c.413G>A​(p.Arg138His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,603,788 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. R138C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0059 (13 hom., cov: 34)
  • Exomes 𝑓: 0.00057 (7 hom.)
• Consequence: KRTAP4-1 NM_001386841.1 missense
• Clinical Significance: Not reported in ClinVar
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049245656).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0059 (898/152306) while in subpopulation AFR AF = 0.0206 (858/41554). AF 95% confidence interval is 0.0195. There are 13 homozygotes in GnomAd4. There are 426 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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>A	p.Arg138His	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>A	p.Arg138His	missense	Exon 1 of 1	ENSP00000381489.1	Q9BYQ7

Frequencies

GnomAD3 genomes AF: 0.00586 AC: 892 AN: 152188 Hom.: 13 Cov.: 34

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00141 AC: 346 AN: 244672 AF XY: 0.00113

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.000669

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000722

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000573 AC: 832 AN: 1451482 Hom.: 7 Cov.: 77 AF XY: 0.000473 AC XY: 341 AN XY: 720248

African (AFR) AF: 0.0199 AC: 664 AN: 33284

American (AMR) AF: 0.000810 AC: 36 AN: 44468

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

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39482

South Asian (SAS) AF: 0.0000470 AC: 4 AN: 85062

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

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5728

European-Non Finnish (NFE) AF: 0.0000380 AC: 42 AN: 1105040

Other (OTH) AF: 0.00139 AC: 83 AN: 59908

GnomAD4 genome AF: 0.00590 AC: 898 AN: 152306 Hom.: 13 Cov.: 34 AF XY: 0.00572 AC XY: 426 AN XY: 74482

African (AFR) AF: 0.0206 AC: 858 AN: 41554

American (AMR) AF: 0.00209 AC: 32 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00134 Hom.: 3

Bravo AF: 0.00667

ESP6500AA AF: 0.0185 AC: 80

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00181 AC: 219

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.2
DANN	Benign	0.90
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.93	T
PhyloP100		-0.37
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.028
Sift	Uncertain	0.024	D
Sift4G	Benign	0.066	T
Polyphen		0.019	B
Vest4		0.18
MVP		0.030
MPC		0.20
ClinPred		0.016	T
GERP RS		1.9
PromoterAI		0.013	Neutral
Varity_R		0.059
gMVP		0.055
Mutation Taster		=92/8	polymorphism

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; COSMIC: COSV66648133; COSMIC: COSV66648133;