11-66843021-C-G

Variant names:

• chr11-66843021-C-G
• rs369989753
• NM_001302084.2:c.1422C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001302084.2(TOP6BL):​c.1422C>G​(p.His474Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,401,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H474H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TOP6BL NM_001302084.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08575338).

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.1422C>G	p.His474Gln	missense	Exon 14 of 15	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.1773C>G	p.His591Gln	missense	Exon 16 of 17	NP_078926.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP6BL	ENST00000540737.7	TSL:2 MANE Select	c.1422C>G	p.His474Gln	missense	Exon 14 of 15	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525449.6	TSL:1	c.1344C>G	p.His448Gln	missense	Exon 14 of 15	ENSP00000434648.2	A0A140TA08
	TOP6BL	ENST00000525908.6	TSL:2	c.1773C>G	p.His591Gln	missense	Exon 16 of 17	ENSP00000432039.3	A0A2U3TZP7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000654 AC: 1 AN: 152882 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000172

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1401462 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 691868

African (AFR) AF: 0.00 AC: 0 AN: 31876

American (AMR) AF: 0.00 AC: 0 AN: 36136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25204

East Asian (EAS) AF: 0.00 AC: 0 AN: 36176

South Asian (SAS) AF: 0.00 AC: 0 AN: 80050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4416

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082822

Other (OTH) AF: 0.00 AC: 0 AN: 58028

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.1
DANN	Benign	0.93
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.0
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.022
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		0.062	B
Vest4		0.14
MVP		0.076
MPC		0.33
ClinPred		0.23	T
GERP RS		1.1
PromoterAI		0.019	Neutral
gMVP		0.18
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs369989753; hg19: chr11-66610492;