17-41249877-C-T

Variant names:

• chr17-41249877-C-T
• rs375235134
• NM_033191.3:c.157C>T

Variant summary

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

The NM_033191.3(KRTAP9-4):​c.157C>T​(p.Arg53Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000152 in 1,541,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R53H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: KRTAP9-4 NM_033191.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.299
• Publications: 1 publications found

Genes affected

KRTAP9-4 (HGNC:18902): (keratin associated protein 9-4) 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, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.047612846).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033191.3. 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
	KRTAP9-4	NM_033191.3	MANE Select	c.157C>T	p.Arg53Cys	missense	Exon 1 of 1	NP_149461.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP9-4	ENST00000334109.3	TSL:6 MANE Select	c.157C>T	p.Arg53Cys	missense	Exon 1 of 1	ENSP00000334922.2	Q9BYQ2

Frequencies

GnomAD3 genomes AF: 0.0000856 AC: 13 AN: 151946 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000677 AC: 17 AN: 251276 AF XY: 0.0000736

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000160 AC: 222 AN: 1389872 Hom.: 0 Cov.: 188 AF XY: 0.000152 AC XY: 105 AN XY: 692862

African (AFR) AF: 0.00 AC: 0 AN: 32028

American (AMR) AF: 0.0000493 AC: 2 AN: 40566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24834

East Asian (EAS) AF: 0.00108 AC: 41 AN: 37936

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5344

European-Non Finnish (NFE) AF: 0.000157 AC: 166 AN: 1055026

Other (OTH) AF: 0.000209 AC: 12 AN: 57318

GnomAD4 genome AF: 0.0000856 AC: 13 AN: 151946 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74198

African (AFR) AF: 0.0000483 AC: 2 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000109

EpiControl AF: 0.00

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	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.0069	N
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.30
PrimateAI	Benign	0.17	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.037
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0	B
Vest4		0.10
MVP		0.29
MPC		0.12
ClinPred		0.10	T
GERP RS		1.6
PromoterAI		0.0032	Neutral
Varity_R		0.12
gMVP		0.063
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: rs375235134; hg19: chr17-39406129; COSMIC: COSV61898674;