chr17-41118089-C-T

Variant names:

• chr17-41118089-C-T
• rs567313634
• NM_033059.4:c.227G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033059.4(KRTAP4-11):​c.227G>A​(p.Arg76His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000259 in 1,583,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: KRTAP4-11 NM_033059.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.269
• Publications: 3 publications found

Genes affected

KRTAP4-11 (HGNC:18911): (keratin associated protein 4-11) 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, Mar 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.024680257).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033059.4. 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
	KRTAP4-11	NM_033059.4	MANE Select	c.227G>A	p.Arg76His	missense	Exon 1 of 1	NP_149048.2	Q9BYQ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-11	ENST00000391413.4	TSL:6 MANE Select	c.227G>A	p.Arg76His	missense	Exon 1 of 1	ENSP00000375232.2	Q9BYQ6

Frequencies

GnomAD3 genomes AF: 0.0000534 AC: 8 AN: 149734 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000971

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000403 AC: 10 AN: 248226 AF XY: 0.0000518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000437

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000230 AC: 33 AN: 1433748 Hom.: 0 Cov.: 223 AF XY: 0.0000267 AC XY: 19 AN XY: 712300

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

African (AFR) AF: 0.00 AC: 0 AN: 28360

American (AMR) AF: 0.00 AC: 0 AN: 42726

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25516

East Asian (EAS) AF: 0.000539 AC: 21 AN: 38944

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81852

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52920

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5634

European-Non Finnish (NFE) AF: 0.00000637 AC: 7 AN: 1099010

Other (OTH) AF: 0.00 AC: 0 AN: 58786

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000368938), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000534 AC: 8 AN: 149844 Hom.: 0 Cov.: 34 AF XY: 0.0000682 AC XY: 5 AN XY: 73314

African (AFR) AF: 0.0000254 AC: 1 AN: 39318

American (AMR) AF: 0.00 AC: 0 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000973 AC: 5 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000150 AC: 18

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	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.27
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.023
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.028	B
Vest4		0.12
MutPred		0.50		Loss of phosphorylation at S78 (P = 0.0693)
MVP		0.13
MPC		0.0084
ClinPred		0.33	T
GERP RS		1.6
PromoterAI		0.0070	Neutral
Varity_R		0.074
gMVP		0.047
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs567313634; hg19: chr17-39274341; COSMIC: COSV66948602;