chr11-66756337-CTT-C

Variant names:

• chr11-66756337-CTT-C
• rs538618909
• NM_001302084.2:c.-29-2697_-29-2696delTT

Variant summary

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

The NM_024650.4(TOP6BL):​c.170-7_170-6delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 939,494 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: 𝑓 0.0 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000026 (0 hom.)
  • Failed GnomAD Quality Control
• 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.-29-2697_-29-2696delTT		intron	N/A	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.170-7_170-6delTT		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_-29-2704delTT		intron	N/A	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525449.6	TSL:1	c.-149-15_-149-14delTT		intron	N/A	ENSP00000434648.2	A0A140TA08
	TOP6BL	ENST00000525908.6	TSL:2	c.170-15_170-14delTT		intron	N/A	ENSP00000432039.3	A0A2U3TZP7

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 149140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000315 AC: 8 AN: 25382 AF XY: 0.000504

Gnomad AFR exome AF: 0.000883

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.000547

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000255 AC: 24 AN: 939494 Hom.: 0 AF XY: 0.0000418 AC XY: 19 AN XY: 454532

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

African (AFR) AF: 0.0000546 AC: 1 AN: 18308

American (AMR) AF: 0.00 AC: 0 AN: 14528

Ashkenazi Jewish (ASJ) AF: 0.0000887 AC: 1 AN: 11270

East Asian (EAS) AF: 0.000133 AC: 1 AN: 7526

South Asian (SAS) AF: 0.0000928 AC: 5 AN: 53884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9270

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

European-Non Finnish (NFE) AF: 0.0000190 AC: 15 AN: 788902

Other (OTH) AF: 0.0000298 AC: 1 AN: 33538

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 149140 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 72638

African (AFR) AF: 0.00 AC: 0 AN: 40692

American (AMR) AF: 0.00 AC: 0 AN: 14880

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9990

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67090

Other (OTH) AF: 0.00 AC: 0 AN: 2026

Alfa AF: 0.000241 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.75
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;