17-41190155-G-T

Variant names:

• chr17-41190155-G-T
• rs768451282
• NM_001190460.1:c.269G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001190460.1(KRTAP9-1):​c.269G>T​(p.Cys90Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C90S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRTAP9-1 NM_001190460.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.76
• Publications: 0 publications found

Genes affected

KRTAP9-1 (HGNC:18912): (keratin associated protein 9-1) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001190460.1. 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
	KRTAP9-1	NM_001190460.1	MANE Select	c.269G>T	p.Cys90Phe	missense	Exon 1 of 1	NP_001177389.1	A8MXZ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP9-1	ENST00000398470.1	TSL:6 MANE Select	c.269G>T	p.Cys90Phe	missense	Exon 1 of 1	ENSP00000381488.1	A8MXZ3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151946 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248952 AF XY: 0.00

Gnomad AFR exome AF: 0.0000641

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.10e-7 AC: 1 AN: 1408104 Hom.: 0 Cov.: 130 AF XY: 0.00 AC XY: 0 AN XY: 698494

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

African (AFR) AF: 0.0000319 AC: 1 AN: 31370

American (AMR) AF: 0.00 AC: 0 AN: 39448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24788

East Asian (EAS) AF: 0.00 AC: 0 AN: 35712

South Asian (SAS) AF: 0.00 AC: 0 AN: 76882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085170

Other (OTH) AF: 0.00 AC: 0 AN: 57742

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151946 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74214

African (AFR) AF: 0.0000483 AC: 2 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.064
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0025	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		2.8
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-9.5	D
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Vest4		0.24
MutPred		0.73		Gain of glycosylation at S93 (P = 0.1082)
MVP		0.26
MPC		0.036
ClinPred		0.97	D
GERP RS		2.8
PromoterAI		-0.0014	Neutral
Varity_R		0.78
gMVP		0.23

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: rs768451282; hg19: chr17-39346407; COSMIC: COSV107383718; COSMIC: COSV107383718;