17-41140246-C-T

Variant names:

• chr17-41140246-C-T
• rs541513264
• NM_030976.2:c.242G>A

Variant summary

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

The NM_030976.2(KRTAP4-6):​c.242G>A​(p.Arg81His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000597 in 1,592,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. R81C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: KRTAP4-6 NM_030976.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.612
• Publications: 6 publications found

Genes affected

KRTAP4-6 (HGNC:18909): (keratin associated protein 4-6) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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=0.107390344).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030976.2. 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
	KRTAP4-6	NM_030976.2	MANE Select	c.242G>A	p.Arg81His	missense	Exon 1 of 1	NP_112238.1	Q9BYQ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-6	ENST00000345847.5	TSL:6 MANE Select	c.242G>A	p.Arg81His	missense	Exon 1 of 1	ENSP00000328270.5	Q9BYQ5

Frequencies

GnomAD3 genomes AF: 0.0000923 AC: 14 AN: 151756 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.0000762 AC: 19 AN: 249250 AF XY: 0.0000443

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000562 AC: 81 AN: 1440506 Hom.: 0 Cov.: 37 AF XY: 0.0000446 AC XY: 32 AN XY: 716784

African (AFR) AF: 0.0000956 AC: 3 AN: 31394

American (AMR) AF: 0.0000696 AC: 3 AN: 43122

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25540

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39454

South Asian (SAS) AF: 0.000118 AC: 10 AN: 84542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.0000491 AC: 54 AN: 1099380

Other (OTH) AF: 0.000102 AC: 6 AN: 58880

GnomAD4 genome AF: 0.0000922 AC: 14 AN: 151866 Hom.: 0 Cov.: 30 AF XY: 0.0000673 AC XY: 5 AN XY: 74260

African (AFR) AF: 0.000121 AC: 5 AN: 41364

American (AMR) AF: 0.0000655 AC: 1 AN: 15260

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

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

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67944

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.0000411 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000833 AC: 10

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	0.16
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.035	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.61
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.070
Sift	Benign	0.049	D
Sift4G	Benign	0.089	T
Vest4		0.13
MVP		0.13
MPC		0.065
ClinPred		0.21	T
GERP RS		0.95
PromoterAI		0.018	Neutral
Varity_R		0.083
gMVP		0.090
Mutation Taster		=95/5	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: rs541513264; hg19: chr17-39296498; COSMIC: COSV61981163;