rs28622379

chr7-33367761-T-Cchr7-33367761-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_198428.3(BBS9):c.1694-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,613,348 control chromosomes in the GnomAD database, including 169 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (146 hom.)
• Consequence: BBS9 NM_198428.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001122
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.788

Genes affected

BBS9 (HGNC:30000): (Bardet-Biedl syndrome 9) This gene is downregulated by parathyroid hormone in osteoblastic cells, and therefore is thought to be involved in parathyroid hormone action in bones. The exact function of this gene has not yet been determined. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-33367761-T-C is Benign according to our data. Variant chr7-33367761-T-C is described in ClinVar as [Benign]. Clinvar id is 263121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-33367761-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00851 (1296/152280) while in subpopulation SAS AF= 0.0456 (220/4822). AF 95% confidence interval is 0.0407. There are 23 homozygotes in gnomad4. There are 658 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS9	NM_198428.3	c.1694-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000242067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS9	ENST00000242067.11	c.1694-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_198428.3	P3

Frequencies

GnomAD3 genomes AF: 0.00851 AC: 1295 AN: 152162 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.0456

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00905 AC: 2275 AN: 251336 Hom.: 45 AF XY: 0.0109 AC XY: 1484 AN XY: 135826

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.00761

Gnomad SAS exome AF: 0.0433

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00767

GnomAD4 exome AF: 0.00472 AC: 6900 AN: 1461068 Hom.: 146 Cov.: 30 AF XY: 0.00602 AC XY: 4379 AN XY: 726890

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.0181

Gnomad4 EAS exome AF: 0.00333

Gnomad4 SAS exome AF: 0.0455

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000825

Gnomad4 OTH exome AF: 0.00767

GnomAD4 genome AF: 0.00851 AC: 1296 AN: 152280 Hom.: 23 Cov.: 32 AF XY: 0.00884 AC XY: 658 AN XY: 74460

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.0456

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00322 Hom.: 3

Bravo AF: 0.00794

Asia WGS AF: 0.0260 AC: 89 AN: 3474

EpiCase AF: 0.00251

EpiControl AF: 0.00255

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Bardet-Biedl syndrome 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.1
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.0		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: rs28622379; hg19: chr7-33407373;