Genetic Variant TOP6BL:p.Val492Val (chr11-66843174-G-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_001302084.2(TOP6BL):c.1476G>C(p.Val492Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 1,610,532 control chromosomes in the GnomAD database, including 51,072 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.24 ( 4431 hom., cov: 33)

Exomes 𝑓: 0.25 ( 46641 hom. )

Consequence

TOP6BL
NM_001302084.2 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.379

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:

RCE1 (HGNC:13721): (Ras converting CAAX endopeptidase 1) This gene encodes an integral membrane protein which is classified as a member of the metalloproteinase family. This enzyme is thought to function in the maintenance and processing of CAAX-type prenylated proteins. [provided by RefSeq, Jul 2008]

RCE1 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=-0.66).

BP6

Variant 11-66843174-G-C is Benign according to our data. Variant chr11-66843174-G-C is described in ClinVar as [Benign]. Clinvar id is 3060507.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=-0.379 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP6BL	NM_001302084.2 link	c.1476G>C	p.Val492Val	synonymous_variant	Exon 15 of 15	ENST00000540737.7	NP_001289013.1	Q8N6T0B4DXL1
TOP6BL	NM_024650.4 link	c.1827G>C	p.Val609Val	synonymous_variant	Exon 17 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.1476G>C	p.Val492Val	synonymous_variant	Exon 15 of 15	2	NM_001302084.2	ENSP00000444319.1		B4DXL1
C11orf80	ENST00000525449.6 link	c.1398G>C	p.Val466Val	synonymous_variant	Exon 15 of 15	1		ENSP00000434648.2		A0A140TA08

Frequencies

GnomAD3 genomes

AF:

0.240

AC:

36485

AN:

152072

Hom.:

4434

Cov.:

show subpopulations

Gnomad AFR

AF:

0.228

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.313

Gnomad EAS

AF:

0.160

Gnomad SAS

AF:

0.140

Gnomad FIN

AF:

0.267

Gnomad MID

AF:

0.320

Gnomad NFE

AF:

0.259

Gnomad OTH

AF:

0.255

GnomAD3 exomes

AF:

0.223

AC:

53666

AN:

241070

Hom.:

6403

AF XY:

0.225

AC XY:

29731

AN XY:

132040

show subpopulations

Gnomad AFR exome

AF:

0.222

Gnomad AMR exome

AF:

0.145

Gnomad ASJ exome

AF:

0.314

Gnomad EAS exome

AF:

0.171

Gnomad SAS exome

AF:

0.130

Gnomad FIN exome

AF:

0.272

Gnomad NFE exome

AF:

0.263

Gnomad OTH exome

AF:

0.243

GnomAD4 exome

AF:

0.249

AC:

363098

AN:

1458342

Hom.:

46641

Cov.:

AF XY:

0.247

AC XY:

179189

AN XY:

725340

show subpopulations

Gnomad4 AFR exome

AF:

0.225

Gnomad4 AMR exome

AF:

0.152

Gnomad4 ASJ exome

AF:

0.306

Gnomad4 EAS exome

AF:

0.154

Gnomad4 SAS exome

AF:

0.133

Gnomad4 FIN exome

AF:

0.269

Gnomad4 NFE exome

AF:

0.264

Gnomad4 OTH exome

AF:

0.247

GnomAD4 genome

AF:

0.240

AC:

36483

AN:

152190

Hom.:

4431

Cov.:

AF XY:

0.238

AC XY:

17726

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.228

Gnomad4 AMR

AF:

0.210

Gnomad4 ASJ

AF:

0.313

Gnomad4 EAS

AF:

0.160

Gnomad4 SAS

AF:

0.140

Gnomad4 FIN

AF:

0.267

Gnomad4 NFE

AF:

0.259

Gnomad4 OTH

AF:

0.256

Alfa

AF:

0.262

Hom.:

1708

Bravo

AF:

0.237

Asia WGS

AF:

0.155

AC:

541

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TOP6BL-related disorder

Benign:1

Oct 21, 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

-0.66

CADD

Benign

5.5

DANN

Benign

0.59

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