11-66756337-CTTT-CTTTT

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS1

The NM_024650.4(TOP6BL):​c.170-6dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 1,006,230 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 0.00056 (0 hom., cov: 31)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: TOP6BL NM_024650.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.538

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0208 (17834/857042) while in subpopulation SAS AF= 0.0358 (1797/50166). AF 95% confidence interval is 0.0344. There are 0 homozygotes in gnomad4_exome. There are 9049 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP6BL	NM_001302084.2	c.-29-2696dupT		intron_variant	Intron 1 of 14	ENST00000540737.7	NP_001289013.1
TOP6BL	NM_024650.4	c.170-6dupT		splice_region_variant, intron_variant	Intron 2 of 16		NP_078926.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C11orf80	ENST00000540737.7	c.-29-2706_-29-2705insT		intron_variant	Intron 1 of 14	2	NM_001302084.2	ENSP00000444319.1
C11orf80	ENST00000525449.6	c.-149-16_-149-15insT		intron_variant	Intron 1 of 14	1		ENSP00000434648.2

Frequencies

GnomAD3 genomes AF: 0.000550 AC: 82 AN: 149092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000516

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000605

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000586

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.000301

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000626

Gnomad OTH AF: 0.000987

GnomAD3 exomes AF: 0.0831 AC: 2109 AN: 25382 Hom.: 0 AF XY: 0.0860 AC XY: 1195 AN XY: 13902

Gnomad AFR exome AF: 0.0901

Gnomad AMR exome AF: 0.0758

Gnomad ASJ exome AF: 0.0919

Gnomad EAS exome AF: 0.0838

Gnomad SAS exome AF: 0.0812

Gnomad FIN exome AF: 0.0890

Gnomad NFE exome AF: 0.0846

Gnomad OTH exome AF: 0.0768

GnomAD4 exome AF: 0.0208 AC: 17834 AN: 857042 Hom.: 0 Cov.: 24 AF XY: 0.0218 AC XY: 9049 AN XY: 415210

Gnomad4 AFR exome AF: 0.0211

Gnomad4 AMR exome AF: 0.0354

Gnomad4 ASJ exome AF: 0.0326

Gnomad4 EAS exome AF: 0.0317

Gnomad4 SAS exome AF: 0.0358

Gnomad4 FIN exome AF: 0.0404

Gnomad4 NFE exome AF: 0.0188

Gnomad4 OTH exome AF: 0.0233

GnomAD4 genome AF: 0.000556 AC: 83 AN: 149188 Hom.: 0 Cov.: 31 AF XY: 0.000495 AC XY: 36 AN XY: 72712

Gnomad4 AFR AF: 0.000539

Gnomad4 AMR AF: 0.000604

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000588

Gnomad4 SAS AF: 0.000214

Gnomad4 FIN AF: 0.000301

Gnomad4 NFE AF: 0.000626

Gnomad4 OTH AF: 0.000978

ClinVar

Not reported in ClinVar

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

LitVar

Other links and lift over

dbSNP: rs538618909; hg19: chr11-66523808;