11-66842871-CAA-C

Variant names:

• chr11-66842871-CAA-C
• NM_001302084.2:c.1273_1274delAA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001302084.2(TOP6BL):​c.1273_1274delAA​(p.Lys425GlufsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000352 in 1,419,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TOP6BL NM_001302084.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.79
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-66842871-CAA-C is Pathogenic according to our data. Variant chr11-66842871-CAA-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2571602.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1273_1274delAA	p.Lys425GlufsTer41	frameshift	Exon 14 of 15	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.1624_1625delAA	p.Lys542GlufsTer41	frameshift	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.1273_1274delAA	p.Lys425GlufsTer41	frameshift	Exon 14 of 15	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525449.6	TSL:1	c.1195_1196delAA	p.Lys399GlufsTer41	frameshift	Exon 14 of 15	ENSP00000434648.2	A0A140TA08
	TOP6BL	ENST00000525908.6	TSL:2	c.1624_1625delAA	p.Lys542GlufsTer41	frameshift	Exon 16 of 17	ENSP00000432039.3	A0A2U3TZP7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000352 AC: 5 AN: 1419834 Hom.: 0 AF XY: 0.00000427 AC XY: 3 AN XY: 702490

African (AFR) AF: 0.00 AC: 0 AN: 32264

American (AMR) AF: 0.00 AC: 0 AN: 38196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25370

East Asian (EAS) AF: 0.00 AC: 0 AN: 37170

South Asian (SAS) AF: 0.00 AC: 0 AN: 81098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5342

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1092318

Other (OTH) AF: 0.0000340 AC: 2 AN: 58738

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hydatidiform mole, recurrent, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr11-66610342;