11-66756337-CTTT-CTT

Variant names:

• chr11-66756337-CT-C
• rs538618909
• NM_001302084.2:c.-29-2696delT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_024650.4(TOP6BL):​c.170-6delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,081,708 control chromosomes in the GnomAD database, including 84 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (12 hom., cov: 31)
  • Exomes 𝑓: 0.016 (72 hom.)
• Consequence: TOP6BL NM_024650.4 splice_region, 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 11-66756337-CT-C is Benign according to our data. Variant chr11-66756337-CT-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3055765.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0111 (1659/149214) while in subpopulation NFE AF = 0.0159 (1066/67076). AF 95% confidence interval is 0.0151. There are 12 homozygotes in GnomAd4. There are 760 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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.-29-2696delT		intron	N/A	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.170-6delT		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.-29-2705delT		intron	N/A	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525449.6	TSL:1	c.-149-15delT		intron	N/A	ENSP00000434648.2	A0A140TA08
	TOP6BL	ENST00000525908.6	TSL:2	c.170-15delT		intron	N/A	ENSP00000432039.3	A0A2U3TZP7

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1659 AN: 149118 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.00546

Gnomad AMI AF: 0.0298

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0134

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.00470

Gnomad FIN AF: 0.00130

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0411 AC: 1044 AN: 25382 AF XY: 0.0407

Gnomad AFR exome AF: 0.0300

Gnomad AMR exome AF: 0.0426

Gnomad ASJ exome AF: 0.0536

Gnomad EAS exome AF: 0.0153

Gnomad FIN exome AF: 0.0309

Gnomad NFE exome AF: 0.0483

Gnomad OTH exome AF: 0.0430

GnomAD4 exome AF: 0.0158 AC: 14737 AN: 932494 Hom.: 72 Cov.: 24 AF XY: 0.0158 AC XY: 7123 AN XY: 450934

African (AFR) AF: 0.00721 AC: 131 AN: 18170

American (AMR) AF: 0.0198 AC: 284 AN: 14360

Ashkenazi Jewish (ASJ) AF: 0.0197 AC: 219 AN: 11140

East Asian (EAS) AF: 0.00538 AC: 40 AN: 7438

South Asian (SAS) AF: 0.00995 AC: 529 AN: 53158

European-Finnish (FIN) AF: 0.00878 AC: 80 AN: 9114

Middle Eastern (MID) AF: 0.0168 AC: 38 AN: 2256

European-Non Finnish (NFE) AF: 0.0164 AC: 12874 AN: 783604

Other (OTH) AF: 0.0163 AC: 542 AN: 33254

GnomAD4 genome AF: 0.0111 AC: 1659 AN: 149214 Hom.: 12 Cov.: 31 AF XY: 0.0104 AC XY: 760 AN XY: 72734

African (AFR) AF: 0.00544 AC: 222 AN: 40798

American (AMR) AF: 0.0153 AC: 228 AN: 14894

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 46 AN: 3440

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5104

South Asian (SAS) AF: 0.00470 AC: 22 AN: 4680

European-Finnish (FIN) AF: 0.00130 AC: 13 AN: 9982

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.0159 AC: 1066 AN: 67076

Other (OTH) AF: 0.0147 AC: 30 AN: 2044

Alfa AF: 0.0107 Hom.: 0

Bravo AF: 0.0125

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

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

dbSNP: rs538618909; hg19: chr11-66523808;