chr11-66756337-CTTT-C

Variant names:

• chr11-66756337-CTTT-C
• rs538618909
• NM_001302084.2:c.-29-2698_-29-2696delTTT

Variant summary

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

The NM_024650.4(TOP6BL):​c.170-8_170-6delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000106 in 939,896 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: TOP6BL NM_024650.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.750
• 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]

TOP6BL Gene-Disease associations (from GenCC):

• hydatidiform mole, recurrent, 4

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024650.4. 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.-29-2698_-29-2696delTTT		intron	N/A	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.170-8_170-6delTTT		splice_region intron	N/A	NP_078926.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP6BL	ENST00000540737.7	TSL:2 MANE Select	c.-29-2705_-29-2703delTTT		intron	N/A	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525449.6	TSL:1	c.-149-15_-149-13delTTT		intron	N/A	ENSP00000434648.2	A0A140TA08
	TOP6BL	ENST00000525908.6	TSL:2	c.170-15_170-13delTTT		intron	N/A	ENSP00000432039.3	A0A2U3TZP7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000106 AC: 1 AN: 939896 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 454788

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18312

American (AMR) AF: 0.00 AC: 0 AN: 14540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11280

East Asian (EAS) AF: 0.00 AC: 0 AN: 7536

South Asian (SAS) AF: 0.00 AC: 0 AN: 53976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2268

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 789138

Other (OTH) AF: 0.00 AC: 0 AN: 33562

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs538618909; hg19: chr11-66523808;