Genetic Variant KRTAP4-8:p.Cys65_Arg66insArgProSerCysCysIleSerSerCysCys (chr17-41097890-A-ACAGCAGCTGGAGATGCAGCAGCTGGGGCGG) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_031960.3(KRTAP4-8):c.194_195insCCGCCCCAGCTGCTGCATCTCCAGCTGCTG(p.Cys65_Arg66insArgProSerCysCysIleSerSerCysCys) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 41,636 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00065 ( 18 hom. )

Failed GnomAD Quality Control

Consequence

KRTAP4-8
NM_031960.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.22

Publications

0 publications found

Variant links:

Genes affected

KRTAP4-8 (HGNC:17230): (keratin associated protein 4-8) Involved in aging and hair cycle. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP4-8 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_031960.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_031960.3.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031960.3. 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
	KRTAP4-8	NM_031960.3	MANE Select	c.194_195insCCGCCCCAGCTGCTGCATCTCCAGCTGCTG	p.Cys65_Arg66insArgProSerCysCysIleSerSerCysCys	disruptive_inframe_insertion	Exon 1 of 1	NP_114166.1	Q9BYQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-8	ENST00000333822.5	TSL:6 MANE Select	c.194_195insCCGCCCCAGCTGCTGCATCTCCAGCTGCTG	p.Cys65_Arg66insArgProSerCysCysIleSerSerCysCys	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000328444.4	Q9BYQ9

Frequencies

GnomAD3 genomes

AF:

0.000216

AC:

AN:

41624

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000137

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000439

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000335

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000963

AC:

AN:

51934

AF XY:

0.000107

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000280

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000154

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000649

AC:

451

AN:

694730

Hom.:

Cov.:

104

AF XY:

0.000697

AC XY:

244

AN XY:

349984

show subpopulations

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

African (AFR)

AF:

0.000713

AC:

AN:

12630

American (AMR)

AF:

0.000388

AC:

AN:

20618

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

13926

East Asian (EAS)

AF:

0.000208

AC:

AN:

28892

South Asian (SAS)

AF:

0.00179

AC:

AN:

48704

European-Finnish (FIN)

AF:

0.00124

AC:

AN:

26594

Middle Eastern (MID)

AF:

0.00130

AC:

AN:

2312

European-Non Finnish (NFE)

AF:

0.000542

AC:

276

AN:

509694

Other (OTH)

AF:

0.000670

AC:

AN:

31360

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.303

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000216

AC:

AN:

41636

Hom.:

Cov.:

AF XY:

0.000246

AC XY:

AN XY:

20330

show subpopulations

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

African (AFR)

AF:

0.000137

AC:

AN:

7320

American (AMR)

AF:

0.00

AC:

AN:

4710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1108

East Asian (EAS)

AF:

0.000440

AC:

AN:

2274

South Asian (SAS)

AF:

0.00

AC:

AN:

1742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000335

AC:

AN:

20900

Other (OTH)

AF:

0.00

AC:

AN:

576

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000378308), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.292

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.2

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over