17-41097708-C-T

Variant names:

• chr17-41097708-C-T
• rs80168553
• NM_031960.3:c.377G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031960.3(KRTAP4-8):​c.377G>A​(p.Arg126His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 684,524 control chromosomes in the GnomAD database, including 68,158 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. R126L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.53 (18852 hom., cov: 24)
  • Exomes 𝑓: 0.32 (49306 hom.)
• Consequence: KRTAP4-8 NM_031960.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.56

Genes affected

KRTAP4-8 (HGNC:17230): (keratin associated protein 4-8) Involved in aging and hair cycle. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057708025).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-8	NM_031960.3	c.377G>A	p.Arg126His	missense_variant	Exon 1 of 1	ENST00000333822.5	NP_114166.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-8	ENST00000333822.5	c.377G>A	p.Arg126His	missense_variant	Exon 1 of 1	6	NM_031960.3	ENSP00000328444.4

Frequencies

GnomAD3 genomes AF: 0.531 AC: 65613 AN: 123570 Hom.: 18836 Cov.: 24

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.593

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.543

GnomAD3 exomes AF: 0.125 AC: 12610 AN: 100516 Hom.: 4107 AF XY: 0.121 AC XY: 6656 AN XY: 55042

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.0358

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.318 AC: 178437 AN: 560896 Hom.: 49306 Cov.: 25 AF XY: 0.322 AC XY: 92142 AN XY: 285770

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.466

Gnomad4 EAS exome AF: 0.186

Gnomad4 SAS exome AF: 0.294

Gnomad4 FIN exome AF: 0.519

Gnomad4 NFE exome AF: 0.314

Gnomad4 OTH exome AF: 0.369

GnomAD4 genome AF: 0.531 AC: 65627 AN: 123628 Hom.: 18852 Cov.: 24 AF XY: 0.527 AC XY: 31804 AN XY: 60330

Gnomad4 AFR AF: 0.483

Gnomad4 AMR AF: 0.492

Gnomad4 ASJ AF: 0.593

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.443

Gnomad4 FIN AF: 0.586

Gnomad4 NFE AF: 0.580

Gnomad4 OTH AF: 0.541

ExAC AF: 0.0491 AC: 4591

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.7
DANN	Benign	0.93
DEOGEN2	Benign	0.064	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.073	T;T
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Benign	0.065
Sift	Benign	0.070	T;.
Sift4G	Benign	0.13	T;T
Polyphen		0.96	D;.
Vest4		0.053
MPC		0.11
ClinPred		0.060	T
GERP RS		-2.0
Varity_R		0.072
gMVP		0.078

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

LitVar

Other links and lift over

dbSNP: rs80168553; hg19: chr17-39253960; COSMIC: COSV61563885; COSMIC: COSV61563885;