chr11-66842947-G-A

Variant names:

• chr11-66842947-G-A
• rs200048907
• NM_001302084.2:c.1348G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001302084.2(TOP6BL):​c.1348G>A​(p.Glu450Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,556,148 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (37 hom.)
• Consequence: TOP6BL NM_001302084.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.767

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]

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037114918).
• BP6: Variant 11-66842947-G-A is Benign according to our data. Variant chr11-66842947-G-A is described in ClinVar as [Benign]. Clinvar id is 791631.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP6BL	NM_001302084.2	c.1348G>A	p.Glu450Lys	missense_variant	Exon 14 of 15	ENST00000540737.7	NP_001289013.1
TOP6BL	NM_024650.4	c.1699G>A	p.Glu567Lys	missense_variant	Exon 16 of 17		NP_078926.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C11orf80	ENST00000540737.7	c.1348G>A	p.Glu450Lys	missense_variant	Exon 14 of 15	2	NM_001302084.2	ENSP00000444319.1
C11orf80	ENST00000525449.6	c.1270G>A	p.Glu424Lys	missense_variant	Exon 14 of 15	1		ENSP00000434648.2

Frequencies

GnomAD3 genomes AF: 0.00453 AC: 689 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00432 AC: 671 AN: 155476 Hom.: 4 AF XY: 0.00444 AC XY: 376 AN XY: 84656

Gnomad AFR exome AF: 0.00212

Gnomad AMR exome AF: 0.00617

Gnomad ASJ exome AF: 0.00251

Gnomad EAS exome AF: 0.0000891

Gnomad SAS exome AF: 0.00129

Gnomad FIN exome AF: 0.00175

Gnomad NFE exome AF: 0.00673

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00525 AC: 7364 AN: 1403820 Hom.: 37 Cov.: 31 AF XY: 0.00519 AC XY: 3597 AN XY: 693118

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.00558

Gnomad4 ASJ exome AF: 0.00285

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.00603

Gnomad4 OTH exome AF: 0.00559

GnomAD4 genome AF: 0.00452 AC: 688 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00462 AC XY: 344 AN XY: 74496

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00660

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00620 Hom.: 1

Bravo AF: 0.00461

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000678 AC: 2

ESP6500EA AF: 0.00473 AC: 34

ExAC AF: 0.00257 AC: 281

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

TOP6BL-related disorder Benign:1

Apr 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

not provided Benign:1

Dec 28, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Uncertain	1.0
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.72	T;T;T;T;T;T;T
MetaRNN	Benign	0.0037	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.72	.;N;N;N;.;.;.
REVEL	Benign	0.010
Sift	Benign	0.18	.;T;T;T;.;.;.
Sift4G	Benign	0.15	.;.;T;T;.;T;T
Polyphen		0.017	.;.;B;B;.;.;.
Vest4		0.29, 0.32, 0.30, 0.28
MVP		0.048
MPC		0.33
ClinPred		0.0090	T
GERP RS		-1.4
gMVP		0.16

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

Other links and lift over

dbSNP: rs200048907; hg19: chr11-66610418; COSMIC: COSV100547019; COSMIC: COSV100547019;