17-41097889-G-A

Variant names:

• chr17-41097889-G-A
• rs565841925
• NM_031960.3:c.196C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_031960.3(KRTAP4-8):​c.196C>T​(p.Arg66Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000468 in 149,448 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. R66H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000047 (1 hom., cov: 25)
  • Exomes 𝑓: 0.00011 (21 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP4-8 NM_031960.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.02
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0632723).

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.196C>T	p.Arg66Cys	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.196C>T	p.Arg66Cys	missense	Exon 1 of 1	ENSP00000328444.4	Q9BYQ9

Frequencies

GnomAD3 genomes AF: 0.0000469 AC: 7 AN: 149338 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.0000496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000428

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000446

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000491 AC: 12 AN: 244370 AF XY: 0.0000300

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000634

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000108 AC: 147 AN: 1358284 Hom.: 21 Cov.: 98 AF XY: 0.000112 AC XY: 75 AN XY: 671122

African (AFR) AF: 0.0000316 AC: 1 AN: 31656

American (AMR) AF: 0.00 AC: 0 AN: 38522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23470

East Asian (EAS) AF: 0.0000274 AC: 1 AN: 36536

South Asian (SAS) AF: 0.000113 AC: 8 AN: 70896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5088

European-Non Finnish (NFE) AF: 0.000128 AC: 134 AN: 1050088

Other (OTH) AF: 0.0000544 AC: 3 AN: 55130

GnomAD4 genome AF: 0.0000468 AC: 7 AN: 149448 Hom.: 1 Cov.: 25 AF XY: 0.0000549 AC XY: 4 AN XY: 72906

African (AFR) AF: 0.0000495 AC: 2 AN: 40402

American (AMR) AF: 0.00 AC: 0 AN: 14962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.000428 AC: 2 AN: 4672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000446 AC: 3 AN: 67286

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.000143 Hom.: 1

Bravo AF: 0.0000567

ExAC AF: 0.0000662 AC: 6

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	0.17
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		-4.0
PrimateAI	Benign	0.19	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.098
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.045	D
Polyphen		0.65	P
Vest4		0.13
MutPred		0.54		Loss of sheet (P = 0.0817)
MVP		0.095
MPC		0.12
ClinPred		0.36	T
GERP RS		-0.37
PromoterAI		-0.00070	Neutral
Varity_R		0.27
gMVP		0.054
Mutation Taster		=100/0	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: rs565841925; hg19: chr17-39254141; COSMIC: COSV61564812; COSMIC: COSV61564812;