11-66744924-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001302084.2(C11orf80):c.-30+5T>C variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0099 in 1,254,476 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (8 hom., cov: 30)
  • Exomes 𝑓: 0.010 (70 hom.)
• Consequence: C11orf80 NM_001302084.2 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.003980
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.360

Genes affected

C11orf80 (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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 11-66744924-T-C is Benign according to our data. Variant chr11-66744924-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3055893.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0103 (11303/1102516) while in subpopulation SAS AF= 0.0211 (462/21874). AF 95% confidence interval is 0.0195. There are 70 homozygotes in gnomad4_exome. There are 5414 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C11orf80	NM_001302084.2	c.-30+5T>C		splice_donor_5th_base_variant, intron_variant		ENST00000540737.7
C11orf80	NM_024650.3	c.177+5T>C		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C11orf80	ENST00000540737.7	c.-30+5T>C		splice_donor_5th_base_variant, intron_variant		2	NM_001302084.2	A2

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1112 AN: 151842 Hom.: 8 Cov.: 30

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00995

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.0135 AC: 262 AN: 19442 Hom.: 4 AF XY: 0.0140 AC XY: 133 AN XY: 9486

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00323

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0196

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.00991

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.0103 AC: 11303 AN: 1102516 Hom.: 70 Cov.: 33 AF XY: 0.0104 AC XY: 5414 AN XY: 522804

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.00460

Gnomad4 ASJ exome AF: 0.00716

Gnomad4 EAS exome AF: 0.0000753

Gnomad4 SAS exome AF: 0.0211

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00801

GnomAD4 genome AF: 0.00733 AC: 1114 AN: 151960 Hom.: 8 Cov.: 30 AF XY: 0.00778 AC XY: 578 AN XY: 74296

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00295

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.00995

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00835 Hom.: 3

Bravo AF: 0.00600

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TOP6BL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	16
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0040
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.12		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: rs574408551; hg19: chr11-66512395;