chr17-41255636-T-C

Variant names:

• chr17-41255636-T-C
• rs964586183
• NM_030975.2:c.251T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_030975.2(KRTAP9-9):​c.251T>C​(p.Ile84Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000218 in 1,606,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I84N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: KRTAP9-9 NM_030975.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.37
• Publications: 1 publications found

Genes affected

KRTAP9-9 (HGNC:16773): (keratin associated protein 9-9) 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. Alternative haplotypes of this gene are represented in the GRCh38 reference genome assembly. [provided by RefSeq, Dec 2015]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016821176).
• BP6: Variant 17-41255636-T-C is Benign according to our data. Variant chr17-41255636-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2514764.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030975.2. 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
	KRTAP9-9	NM_030975.2	MANE Select	c.251T>C	p.Ile84Thr	missense	Exon 1 of 1	NP_112237.2	Q9BYP9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP9-9	ENST00000394008.1	TSL:6 MANE Select	c.251T>C	p.Ile84Thr	missense	Exon 1 of 1	ENSP00000377576.1	Q9BYP9-3

Frequencies

GnomAD3 genomes AF: 0.0000415 AC: 6 AN: 144730 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000783

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000449

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251430 AF XY: 0.00

Gnomad AFR exome AF: 0.000185

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461762 Hom.: 0 Cov.: 36 AF XY: 0.0000151 AC XY: 11 AN XY: 727182

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1111968

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.0000415 AC: 6 AN: 144730 Hom.: 0 Cov.: 31 AF XY: 0.0000427 AC XY: 3 AN XY: 70320

African (AFR) AF: 0.0000783 AC: 3 AN: 38320

American (AMR) AF: 0.00 AC: 0 AN: 14372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 4732

South Asian (SAS) AF: 0.00 AC: 0 AN: 4450

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 266

European-Non Finnish (NFE) AF: 0.0000449 AC: 3 AN: 66788

Other (OTH) AF: 0.00 AC: 0 AN: 1978

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.065
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.14
DANN	Benign	0.68
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0011	N
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.89	T
PhyloP100		-1.4
PrimateAI	Benign	0.20	T
PROVEAN	Benign	4.0	N
REVEL	Benign	0.034
Sift	Benign	1.0	T
Sift4G	Benign	0.95	T
Vest4		0.026
MVP		0.030
MPC		0.040
ClinPred		0.019	T
GERP RS		-7.5
PromoterAI		-0.0036	Neutral
gMVP		0.025
Mutation Taster		=99/1	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: rs964586183; hg19: chr17-39411888;