Genetic Variant TOP6BL:p.Leu414Leu (chr11-66838438-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001302084.2(TOP6BL):c.1242C>T(p.Leu414Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,613,690 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0089 ( 23 hom., cov: 32)

Exomes 𝑓: 0.00095 ( 20 hom. )

Consequence

TOP6BL
NM_001302084.2 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.0190

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 11-66838438-C-T is Benign according to our data. Variant chr11-66838438-C-T is described in ClinVar as [Benign]. Clinvar id is 3049948.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.019 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00887 (1351/152272) while in subpopulation AFR AF= 0.0302 (1257/41554). AF 95% confidence interval is 0.0289. There are 23 homozygotes in gnomad4. There are 614 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP6BL	NM_001302084.2 link	c.1242C>T	p.Leu414Leu	synonymous_variant	Exon 13 of 15	ENST00000540737.7	NP_001289013.1	Q8N6T0B4DXL1
TOP6BL	NM_024650.4 link	c.1593C>T	p.Leu531Leu	synonymous_variant	Exon 15 of 17		NP_078926.4	Q8N6T0-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C11orf80	ENST00000540737.7 link	c.1242C>T	p.Leu414Leu	synonymous_variant	Exon 13 of 15	2	NM_001302084.2	ENSP00000444319.1		B4DXL1
C11orf80	ENST00000525449.6 link	c.1164C>T	p.Leu388Leu	synonymous_variant	Exon 13 of 15	1		ENSP00000434648.2		A0A140TA08

Frequencies

GnomAD3 genomes

AF:

0.00886

AC:

1348

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0303

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

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:

0.00767

GnomAD3 exomes

AF:

0.00238

AC:

594

AN:

249088

Hom.:

AF XY:

0.00164

AC XY:

221

AN XY:

135140

show subpopulations

Gnomad AFR exome

AF:

0.0324

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000827

GnomAD4 exome

AF:

0.000950

AC:

1388

AN:

1461418

Hom.:

Cov.:

AF XY:

0.000795

AC XY:

578

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.0321

Gnomad4 AMR exome

AF:

0.00212

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.00209

GnomAD4 genome

AF:

0.00887

AC:

1351

AN:

152272

Hom.:

Cov.:

AF XY:

0.00824

AC XY:

614

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0302

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00759

Alfa

AF:

0.00422

Hom.:

Bravo

AF:

0.0112

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TOP6BL-related disorder

Benign:1

Apr 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.91

DANN

Benign

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over