Genetic Variant KRTAP4-8:p.Cys65_Arg66insArgProArgCysCysIleSerSerCysCys (chr17-41097890-A-ACAGCAGCTGGAGATGCAGCATCTGGGGCGG) – 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_195insCCGCCCCAGATGCTGCATCTCCAGCTGCTG(p.Cys65_Arg66insArgProArgCysCysIleSerSerCysCys) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. 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 0.084 ( 501 hom., cov: 26)

Exomes 𝑓: 0.14 ( 28433 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

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_195insCCGCCCCAGATGCTGCATCTCCAGCTGCTG	p.Cys65_Arg66insArgProArgCysCysIleSerSerCysCys	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_195insCCGCCCCAGATGCTGCATCTCCAGCTGCTG	p.Cys65_Arg66insArgProArgCysCysIleSerSerCysCys	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000328444.4	Q9BYQ9

Frequencies

GnomAD3 genomes

AF:

0.0843

AC:

3418

AN:

40532

Hom.:

501

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0664

Gnomad AMI

AF:

0.0947

Gnomad AMR

AF:

0.0993

Gnomad ASJ

AF:

0.0956

Gnomad EAS

AF:

0.0709

Gnomad SAS

AF:

0.0817

Gnomad FIN

AF:

0.0882

Gnomad MID

AF:

0.141

Gnomad NFE

AF:

0.0871

Gnomad OTH

AF:

0.104

GnomAD2 exomes

AF:

0.0399

AC:

2072

AN:

51934

AF XY:

0.0374

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.0437

Gnomad ASJ exome

AF:

0.0285

Gnomad EAS exome

AF:

0.0571

Gnomad FIN exome

AF:

0.00772

Gnomad NFE exome

AF:

0.0330

Gnomad OTH exome

AF:

0.0457

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.144

AC:

94321

AN:

654932

Hom.:

28433

Cov.:

104

AF XY:

0.147

AC XY:

48311

AN XY:

328044

show subpopulations

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

African (AFR)

AF:

0.169

AC:

2097

AN:

12404

American (AMR)

AF:

0.158

AC:

2974

AN:

18834

Ashkenazi Jewish (ASJ)

AF:

0.294

AC:

3829

AN:

13010

East Asian (EAS)

AF:

0.242

AC:

6610

AN:

27340

South Asian (SAS)

AF:

0.0636

AC:

2541

AN:

39958

European-Finnish (FIN)

AF:

0.330

AC:

8055

AN:

24376

Middle Eastern (MID)

AF:

0.248

AC:

540

AN:

2180

European-Non Finnish (NFE)

AF:

0.126

AC:

61519

AN:

487418

Other (OTH)

AF:

0.209

AC:

6156

AN:

29412

⚠️ 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: 0.321

Heterozygous variant carriers

2376

4753

7129

9506

11882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

240

480

720

960

1200

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0842

AC:

3414

AN:

40542

Hom.:

501

Cov.:

AF XY:

0.0861

AC XY:

1708

AN XY:

19840

show subpopulations

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

African (AFR)

AF:

0.0664

AC:

481

AN:

7248

American (AMR)

AF:

0.0988

AC:

454

AN:

4596

Ashkenazi Jewish (ASJ)

AF:

0.0956

AC:

101

AN:

1056

East Asian (EAS)

AF:

0.0710

AC:

159

AN:

2238

South Asian (SAS)

AF:

0.0804

AC:

137

AN:

1704

European-Finnish (FIN)

AF:

0.0882

AC:

227

AN:

2574

Middle Eastern (MID)

AF:

0.155

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0871

AC:

1764

AN:

20250

Other (OTH)

AF:

0.103

AC:

AN:

554

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.321

Heterozygous variant carriers

151

303

454

606

757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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 (auto)

(source)

Splicing

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

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