11-66842871-CAA-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 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

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 id is 2571602.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP6BL	NM_001302084.2	c.1273_1274delAA	p.Lys425GlufsTer41	frameshift_variant	Exon 14 of 15	ENST00000540737.7	NP_001289013.1
TOP6BL	NM_024650.4	c.1624_1625delAA	p.Lys542GlufsTer41	frameshift_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.1273_1274delAA	p.Lys425GlufsTer41	frameshift_variant	Exon 14 of 15	2	NM_001302084.2	ENSP00000444319.1
C11orf80	ENST00000525449.6	c.1195_1196delAA	p.Lys399GlufsTer41	frameshift_variant	Exon 14 of 15	1		ENSP00000434648.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000275

Gnomad4 OTH exome AF: 0.0000340

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hydatidiform mole, recurrent, 4 Pathogenic:1

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Medical Genetics Laboratory, Tarbiat Modares University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-66610342;