17-41097553-C-A

Variant names:

• chr17-41097553-C-A
• rs146385966
• NM_031960.3:c.532G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_031960.3(KRTAP4-8):​c.532G>T​(p.Val178Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00414 in 1,560,196 control chromosomes in the GnomAD database, including 724 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V178M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.033 (518 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (206 hom.)
• Consequence: KRTAP4-8 NM_031960.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.36
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019929707).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031960.3. 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
	KRTAP4-8	NM_031960.3	MANE Select	c.532G>T	p.Val178Leu	missense	Exon 1 of 1	NP_114166.1	Q9BYQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-8	ENST00000333822.5	TSL:6 MANE Select	c.532G>T	p.Val178Leu	missense	Exon 1 of 1	ENSP00000328444.4	Q9BYQ9

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 4953 AN: 148730 Hom.: 516 Cov.: 32

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0280

GnomAD2 exomes AF: 0.00526 AC: 937 AN: 177990 AF XY: 0.00379

Gnomad AFR exome AF: 0.0912

Gnomad AMR exome AF: 0.00394

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000564

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00105 AC: 1483 AN: 1411356 Hom.: 206 Cov.: 88 AF XY: 0.000931 AC XY: 650 AN XY: 698016

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0384 AC: 1048 AN: 27318

American (AMR) AF: 0.00251 AC: 94 AN: 37396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25258

East Asian (EAS) AF: 0.00 AC: 0 AN: 37320

South Asian (SAS) AF: 0.000172 AC: 14 AN: 81174

European-Finnish (FIN) AF: 0.0000396 AC: 2 AN: 50560

Middle Eastern (MID) AF: 0.00406 AC: 23 AN: 5668

European-Non Finnish (NFE) AF: 0.0000965 AC: 105 AN: 1088308

Other (OTH) AF: 0.00338 AC: 197 AN: 58354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0334 AC: 4971 AN: 148840 Hom.: 518 Cov.: 32 AF XY: 0.0318 AC XY: 2317 AN XY: 72770

African (AFR) AF: 0.123 AC: 4712 AN: 38332

American (AMR) AF: 0.0114 AC: 173 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67970

Other (OTH) AF: 0.0277 AC: 58 AN: 2094

Alfa AF: 0.00182 Hom.: 7

ExAC AF: 0.00434 AC: 503

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.061
DANN	Benign	0.82
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.0095	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.025	N
PhyloP100		-3.4
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.0080
Sift	Benign	0.41	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.035
MVP		0.014
MPC		0.088
ClinPred		0.0022	T
GERP RS		-4.1
Varity_R		0.032
gMVP		0.059
Mutation Taster		=100/0	polymorphism (auto)

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: rs146385966; hg19: chr17-39253805; COSMIC: COSV61565748; COSMIC: COSV61565748;