Genetic Variant TOP6BL:p.Ile43Thr (chr11-66788262-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001302084.2(TOP6BL):c.128T>C(p.Ile43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,607,744 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0090 ( 23 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 20 hom. )

Consequence

TOP6BL
NM_001302084.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -2.10

Publications

1 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034433305).

BP6

Variant 11-66788262-T-C is Benign according to our data. Variant chr11-66788262-T-C is described in ClinVar as Benign. ClinVar VariationId is 3050115.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00902 (1374/152348) while in subpopulation AFR AF = 0.0306 (1273/41586). AF 95% confidence interval is 0.0292. There are 23 homozygotes in GnomAd4. There are 626 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001302084.2. 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.128T>C	p.Ile43Thr	missense	Exon 3 of 15	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.479T>C	p.Ile160Thr	missense	Exon 5 of 17	NP_078926.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TOP6BL	ENST00000540737.7	TSL:2 MANE Select	c.128T>C	p.Ile43Thr	missense	Exon 3 of 15	ENSP00000444319.1	Q8N6T0-6
TOP6BL	ENST00000525449.6	TSL:1	c.161T>C	p.Ile54Thr	missense	Exon 4 of 15	ENSP00000434648.2	A0A140TA08
TOP6BL	ENST00000525908.6	TSL:2	c.479T>C	p.Ile160Thr	missense	Exon 5 of 17	ENSP00000432039.3	A0A2U3TZP7

Frequencies

GnomAD3 genomes

AF:

0.00901

AC:

1371

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0306

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

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:

0.000132

Gnomad OTH

AF:

0.00813

GnomAD2 exomes

AF:

0.00243

AC:

602

AN:

248168

AF XY:

0.00166

show subpopulations

Gnomad AFR exome

AF:

0.0328

Gnomad AMR exome

AF:

0.00213

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000996

GnomAD4 exome

AF:

0.000960

AC:

1397

AN:

1455396

Hom.:

Cov.:

AF XY:

0.000809

AC XY:

586

AN XY:

724310

show subpopulations

African (AFR)

AF:

0.0322

AC:

1071

AN:

33308

American (AMR)

AF:

0.00229

AC:

102

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000815

AC:

AN:

85838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000687

AC:

AN:

1106708

Other (OTH)

AF:

0.00223

AC:

134

AN:

60160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00902

AC:

1374

AN:

152348

Hom.:

Cov.:

AF XY:

0.00840

AC XY:

626

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0306

AC:

1273

AN:

41586

American (AMR)

AF:

0.00490

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68020

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

142

213

284

355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00545

Hom.:

Bravo

AF:

0.0115

ESP6500AA

AF:

0.0286

AC:

105

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.00284

AC:

343

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TOP6BL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.36

(source)

DANN

Benign

0.61

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.97

PhyloP100

-2.1

PROVEAN

Benign

-0.58

REVEL

Benign

0.10

Sift

Benign

1.0

Sift4G

Benign

0.67

Vest4

0.24

MVP

0.11

MPC

0.079

ClinPred

0.00088

GERP RS

-5.4

PromoterAI

0.0062

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.044

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

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