NM_001302084.2:c.-29-2697_-29-2696dupTT

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001302084.2(TOP6BL):​c.-29-2697_-29-2696dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 938,592 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TOP6BL NM_001302084.2 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.538
• 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 11-66756337-C-CTT is Benign according to our data. Variant chr11-66756337-C-CTT is described in ClinVar as Likely_benign. ClinVar VariationId is 3038989.Status of the report is no_assertion_criteria_provided, 0 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.-29-2697_-29-2696dupTT		intron	N/A	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.170-7_170-6dupTT		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.-29-2706_-29-2705insTT		intron	N/A	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525449.6	TSL:1	c.-149-16_-149-15insTT		intron	N/A	ENSP00000434648.2	A0A140TA08
	TOP6BL	ENST00000525908.6	TSL:2	c.170-16_170-15insTT		intron	N/A	ENSP00000432039.3	A0A2U3TZP7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00142 AC: 36 AN: 25382 AF XY: 0.00129

Gnomad AFR exome AF: 0.00177

Gnomad AMR exome AF: 0.000815

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00118

Gnomad FIN exome AF: 0.000735

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000167 AC: 157 AN: 938592 Hom.: 0 Cov.: 24 AF XY: 0.000211 AC XY: 96 AN XY: 454066

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

African (AFR) AF: 0.000219 AC: 4 AN: 18288

American (AMR) AF: 0.000414 AC: 6 AN: 14508

Ashkenazi Jewish (ASJ) AF: 0.000533 AC: 6 AN: 11252

East Asian (EAS) AF: 0.00106 AC: 8 AN: 7512

South Asian (SAS) AF: 0.000744 AC: 40 AN: 53786

European-Finnish (FIN) AF: 0.000216 AC: 2 AN: 9260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2262

European-Non Finnish (NFE) AF: 0.000107 AC: 84 AN: 788218

Other (OTH) AF: 0.000209 AC: 7 AN: 33506

⚠️ 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

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TOP6BL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.54
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs538618909; hg19: chr11-66523808;