rs61756571

chr7-33336435-T-C

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.1017-6T>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 0.0445 in 1,610,002 control chromosomes in the GnomAD database, including 1,895 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (136 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1759 hom.)
• Consequence: BBS9 NM_198428.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002977
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.391

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=-0.83).
• BP6: Variant 7-33336435-T-C is Benign according to our data. Variant chr7-33336435-T-C is described in ClinVar as [Benign]. Clinvar id is 263111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-33336435-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0346 (5264/152302) while in subpopulation NFE AF= 0.0494 (3359/68010). AF 95% confidence interval is 0.048. There are 136 homozygotes in gnomad4. There are 2550 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 135 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS9	NM_198428.3	c.1017-6T>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.1017-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_198428.3	P3

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5270 AN: 152184 Hom.: 135 Cov.: 32

Gnomad AFR AF: 0.00904

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.0980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0533

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0494

Gnomad OTH AF: 0.0426

GnomAD3 exomes AF: 0.0393 AC: 9829 AN: 250392 Hom.: 266 AF XY: 0.0400 AC XY: 5415 AN XY: 135298

Gnomad AFR exome AF: 0.00856

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.0934

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0207

Gnomad FIN exome AF: 0.0575

Gnomad NFE exome AF: 0.0537

Gnomad OTH exome AF: 0.0452

GnomAD4 exome AF: 0.0456 AC: 66446 AN: 1457700 Hom.: 1759 Cov.: 30 AF XY: 0.0451 AC XY: 32680 AN XY: 725350

Gnomad4 AFR exome AF: 0.00739

Gnomad4 AMR exome AF: 0.0167

Gnomad4 ASJ exome AF: 0.0954

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0215

Gnomad4 FIN exome AF: 0.0532

Gnomad4 NFE exome AF: 0.0501

Gnomad4 OTH exome AF: 0.0414

GnomAD4 genome AF: 0.0346 AC: 5264 AN: 152302 Hom.: 136 Cov.: 32 AF XY: 0.0342 AC XY: 2550 AN XY: 74478

Gnomad4 AFR AF: 0.00902

Gnomad4 AMR AF: 0.0260

Gnomad4 ASJ AF: 0.0980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.0533

Gnomad4 NFE AF: 0.0494

Gnomad4 OTH AF: 0.0417

Alfa AF: 0.0479 Hom.: 113

Bravo AF: 0.0319

Asia WGS AF: 0.00751 AC: 28 AN: 3478

EpiCase AF: 0.0487

EpiControl AF: 0.0536

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

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	-0.83
Cadd	Benign	1.1
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00030
dbscSNV1_RF	Benign	0.014
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: rs61756571; hg19: chr7-33376047;