Genetic Variant TOP6BL:c.-29-2696dupT (chr11-66756337-C-CT) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024650.4(TOP6BL):c.170-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 1,006,230 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 31)

Exomes 𝑓: 0.021 ( 0 hom. )

Consequence

TOP6BL
NM_024650.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.538

Publications

0 publications found

Variant links:

Genes affected

TOP6BL (HGNC:26197): (TOP6B like initiator of meiotic double strand breaks) Predicted to be involved in meiotic DNA double-strand break formation and reciprocal meiotic recombination. Predicted to be located in chromosome. Implicated in gestational trophoblastic neoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TOP6BL Gene-Disease associations (from GenCC):

hydatidiform mole, recurrent, 4
Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TOP6BL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Variant has high frequency in the SAS (0.0344) population. However there is too low homozygotes in high coverage region: (expected more than 79, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024650.4. 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
	TOP6BL	NM_001302084.2	MANE Select	c.-29-2696dupT		intron	N/A	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.170-6dupT		splice_region intron	N/A	NP_078926.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TOP6BL	ENST00000540737.7	TSL:2 MANE Select	c.-29-2706_-29-2705insT	intron	N/A	ENSP00000444319.1	Q8N6T0-6
TOP6BL	ENST00000525449.6	TSL:1	c.-149-16_-149-15insT	intron	N/A	ENSP00000434648.2	A0A140TA08
TOP6BL	ENST00000525908.6	TSL:2	c.170-16_170-15insT	intron	N/A	ENSP00000432039.3	A0A2U3TZP7

Frequencies

GnomAD3 genomes

AF:

0.000550

AC:

AN:

149092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000516

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000605

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000586

Gnomad SAS

AF:

0.000213

Gnomad FIN

AF:

0.000301

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.000626

Gnomad OTH

AF:

0.000987

GnomAD2 exomes

AF:

0.0831

AC:

2109

AN:

25382

AF XY:

0.0860

show subpopulations

Gnomad AFR exome

AF:

0.0901

Gnomad AMR exome

AF:

0.0758

Gnomad ASJ exome

AF:

0.0919

Gnomad EAS exome

AF:

0.0838

Gnomad FIN exome

AF:

0.0890

Gnomad NFE exome

AF:

0.0846

Gnomad OTH exome

AF:

0.0768

GnomAD4 exome

AF:

0.0208

AC:

17834

AN:

857042

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

9049

AN XY:

415210

show subpopulations

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

African (AFR)

AF:

0.0211

AC:

355

AN:

16864

American (AMR)

AF:

0.0354

AC:

497

AN:

14050

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

345

AN:

10572

East Asian (EAS)

AF:

0.0317

AC:

224

AN:

7056

South Asian (SAS)

AF:

0.0358

AC:

1797

AN:

50166

European-Finnish (FIN)

AF:

0.0404

AC:

355

AN:

8782

Middle Eastern (MID)

AF:

0.0254

AC:

AN:

2086

European-Non Finnish (NFE)

AF:

0.0188

AC:

13489

AN:

716672

Other (OTH)

AF:

0.0233

AC:

719

AN:

30794

⚠️ 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: 0.261

Heterozygous variant carriers

2364

4727

7091

9454

11818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

502

1004

1506

2008

2510

<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:

0.000556

AC:

AN:

149188

Hom.:

Cov.:

AF XY:

0.000495

AC XY:

AN XY:

72712

show subpopulations

African (AFR)

AF:

0.000539

AC:

AN:

40804

American (AMR)

AF:

0.000604

AC:

AN:

14894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.000588

AC:

AN:

5104

South Asian (SAS)

AF:

0.000214

AC:

AN:

4682

European-Finnish (FIN)

AF:

0.000301

AC:

AN:

9978

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000626

AC:

AN:

67050

Other (OTH)

AF:

0.000978

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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

Alfa

AF:

0.0125

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.54

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

11-66756337-CTTT-CTTTT

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