Genetic Variant NM_033187.2:c.285_286insCAGACCACCTGCTGC (chr17-41167887-T-TGCAGCAGGTGGTCTG) – 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_033187.2(KRTAP4-3):c.285_286insCAGACCACCTGCTGC(p.Cys95_Arg96insGlnThrThrCysCys) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 130,666 control chromosomes in the GnomAD database, including 10 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 ( 10 hom., cov: 28)

Exomes 𝑓: 0.00013 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

KRTAP4-3
NM_033187.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.275

Publications

1 publications found

Variant links:

Genes affected

KRTAP4-3 (HGNC:18908): (keratin associated protein 4-3) Involved in aging and hair cycle. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP4-3 links:

Genome browser will be placed here

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_033187.2.

BP6

Variant 17-41167887-T-TGCAGCAGGTGGTCTG is Benign according to our data. Variant chr17-41167887-T-TGCAGCAGGTGGTCTG is described in ClinVar as [Likely_benign]. Clinvar id is 3257581.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-3	NM_033187.2 link	c.285_286insCAGACCACCTGCTGC	p.Cys95_Arg96insGlnThrThrCysCys	conservative_inframe_insertion	Exon 1 of 1	ENST00000391356.4	NP_149443.1	Q9BYR4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-3	ENST00000391356.4 link	c.285_286insCAGACCACCTGCTGC	p.Cys95_Arg96insGlnThrThrCysCys	conservative_inframe_insertion	Exon 1 of 1	6	NM_033187.2	ENSP00000375151.2		Q9BYR4

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

252

AN:

130612

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00856

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000435

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:

0.0000156

Gnomad OTH

AF:

0.00274

GnomAD2 exomes

AF:

0.000140

AC:

AN:

142506

AF XY:

0.0000519

show subpopulations

Gnomad AFR exome

AF:

0.00309

Gnomad AMR exome

AF:

0.000101

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:

0.000129

AC:

184

AN:

1421946

Hom.:

Cov.:

AF XY:

0.000104

AC XY:

AN XY:

703912

show subpopulations

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

African (AFR)

AF:

0.00412

AC:

130

AN:

31584

American (AMR)

AF:

0.000659

AC:

AN:

37950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25454

East Asian (EAS)

AF:

0.00

AC:

AN:

37894

South Asian (SAS)

AF:

0.0000122

AC:

AN:

81778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51098

Middle Eastern (MID)

AF:

0.000642

AC:

AN:

4674

European-Non Finnish (NFE)

AF:

0.00000732

AC:

AN:

1092564

Other (OTH)

AF:

0.000288

AC:

AN:

58950

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.377

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00195

AC:

255

AN:

130666

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

126

AN XY:

63758

show subpopulations

African (AFR)

AF:

0.00865

AC:

243

AN:

28086

American (AMR)

AF:

0.000435

AC:

AN:

13798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3340

East Asian (EAS)

AF:

0.00

AC:

AN:

4682

South Asian (SAS)

AF:

0.00

AC:

AN:

4268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.0000156

AC:

AN:

63940

Other (OTH)

AF:

0.00271

AC:

AN:

1848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0294

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KRTAP4-3: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.28

Mutation Taster

=87/13

polymorphism

(source)

Splicing

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

Publications

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NM_033187.2:c.285_286insCAGACCACCTGCTGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over