rs61756571

Variant names:

• chr7-33336435-T-C
• rs61756571
• NM_198428.3:c.1017-6T>C

Variant summary

Our verdict is Benign. The variant received -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, 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. 3/3 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, intron
• Scores: Splicing: ADA: 0.0002977
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.391
• Publications: 6 publications found

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]

BBS9 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 263111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 136 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS9	NM_198428.3	c.1017-6T>C		splice_region_variant, intron_variant	Intron 9 of 22	ENST00000242067.11	NP_940820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS9	ENST00000242067.11	c.1017-6T>C		splice_region_variant, intron_variant	Intron 9 of 22	1	NM_198428.3	ENSP00000242067.6

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

GnomAD2 exomes AF: 0.0393 AC: 9829 AN: 250392 AF XY: 0.0400

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 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

African (AFR) AF: 0.00739 AC: 247 AN: 33422

American (AMR) AF: 0.0167 AC: 744 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 2485 AN: 26054

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39638

South Asian (SAS) AF: 0.0215 AC: 1851 AN: 86052

European-Finnish (FIN) AF: 0.0532 AC: 2840 AN: 53354

Middle Eastern (MID) AF: 0.0445 AC: 254 AN: 5706

European-Non Finnish (NFE) AF: 0.0501 AC: 55527 AN: 1108542

Other (OTH) AF: 0.0414 AC: 2494 AN: 60260

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

African (AFR) AF: 0.00902 AC: 375 AN: 41588

American (AMR) AF: 0.0260 AC: 398 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0980 AC: 340 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4822

European-Finnish (FIN) AF: 0.0533 AC: 565 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0494 AC: 3359 AN: 68010

Other (OTH) AF: 0.0417 AC: 88 AN: 2112

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome 9 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs61756571; hg19: chr7-33376047;