Genetic Variant NM_031960.3:c.194_195insCCACCCCAGATGCTGCATCTCCAGCTGCTG (chr17-41097890-A-ACAGCAGCTGGAGATGCAGCATCTGGGGTGG) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4BP6_ModerateBS2

The NM_031960.3(KRTAP4-8):c.194_195insCCACCCCAGATGCTGCATCTCCAGCTGCTG(p.Cys65_Arg66insHisProArgCysCysIleSerSerCysCys) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 41,632 control chromosomes in the GnomAD database, including 20 homozygotes. 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. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 20 hom., cov: 26)

Exomes 𝑓: 0.00021 ( 14 hom. )

Failed GnomAD Quality Control

Consequence

KRTAP4-8
NM_031960.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

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:

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ACMG classification

Classification was made for transcript

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

PM4

Nonframeshift variant in NON repetitive region in NM_031960.3.

BP6

Variant 17-41097890-A-ACAGCAGCTGGAGATGCAGCATCTGGGGTGG is Benign according to our data. Variant chr17-41097890-A-ACAGCAGCTGGAGATGCAGCATCTGGGGTGG is described in ClinVar as Likely_benign. ClinVar VariationId is 2647753.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

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_195insCCACCCCAGATGCTGCATCTCCAGCTGCTG	p.Cys65_Arg66insHisProArgCysCysIleSerSerCysCys	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_195insCCACCCCAGATGCTGCATCTCCAGCTGCTG	p.Cys65_Arg66insHisProArgCysCysIleSerSerCysCys	disruptive_inframe_insertion	Exon 1 of 1	ENSP00000328444.4	Q9BYQ9

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

AN:

41620

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000274

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000212

Gnomad ASJ

AF:

0.00181

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00249

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000289

AC:

AN:

51934

AF XY:

0.000320

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000891

Gnomad NFE exome

AF:

0.000307

Gnomad OTH exome

AF:

0.000831

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000208

AC:

145

AN:

695562

Hom.:

Cov.:

104

AF XY:

0.000254

AC XY:

AN XY:

350444

show subpopulations

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

African (AFR)

AF:

0.0000791

AC:

AN:

12636

American (AMR)

AF:

0.0000485

AC:

AN:

20616

Ashkenazi Jewish (ASJ)

AF:

0.000143

AC:

AN:

13948

East Asian (EAS)

AF:

0.00

AC:

AN:

28912

South Asian (SAS)

AF:

0.000143

AC:

AN:

48872

European-Finnish (FIN)

AF:

0.00195

AC:

AN:

26654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2312

European-Non Finnish (NFE)

AF:

0.000155

AC:

AN:

510216

Other (OTH)

AF:

0.0000956

AC:

AN:

31396

⚠️ 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: 0.374

Heterozygous variant carriers

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:

0.00202

AC:

AN:

41632

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

AN XY:

20324

show subpopulations

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

African (AFR)

AF:

0.000273

AC:

AN:

7320

American (AMR)

AF:

0.000212

AC:

AN:

4720

Ashkenazi Jewish (ASJ)

AF:

0.00181

AC:

AN:

1108

East Asian (EAS)

AF:

0.00

AC:

AN:

2274

South Asian (SAS)

AF:

0.00

AC:

AN:

1742

European-Finnish (FIN)

AF:

0.0101

AC:

AN:

2674

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00249

AC:

AN:

20888

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 = 0.000000000140484), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

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

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