7-33155681-CTT-CT

Variant names:

• chr7-33155681-CT-C
• rs747388658
• NM_198428.3:c.310delT

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The NM_001348041.4(BBS9):​c.310delT​(p.Cys104ValfsTer20) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000366 in 1,584,562 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C104C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00023 (2 hom., cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: BBS9 NM_001348041.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.70
• Publications: 2 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: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-33155681-CT-C is Pathogenic according to our data. Variant chr7-33155681-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 462970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348041.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	NM_198428.3	MANE Select	c.310delT	p.Cys104ValfsTer20	frameshift	Exon 4 of 23	NP_940820.1
	BBS9	NM_001348041.4		c.310delT	p.Cys104ValfsTer20	frameshift	Exon 4 of 23	NP_001334970.1
	BBS9	NM_001348036.1		c.310delT	p.Cys104ValfsTer20	frameshift	Exon 4 of 23	NP_001334965.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	ENST00000242067.11	TSL:1 MANE Select	c.310delT	p.Cys104ValfsTer20	frameshift	Exon 4 of 23	ENSP00000242067.6
	BBS9	ENST00000425508.6	TSL:1	c.175delT	p.Cys59ValfsTer20	frameshift	Exon 3 of 9	ENSP00000405151.2
	BBS9	ENST00000433714.5	TSL:1	n.310delT		non_coding_transcript_exon	Exon 4 of 24	ENSP00000412159.1

Frequencies

GnomAD3 genomes AF: 0.000225 AC: 34 AN: 151028 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000725 AC: 18 AN: 248184 AF XY: 0.0000596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000525

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000167 AC: 24 AN: 1433534 Hom.: 0 Cov.: 28 AF XY: 0.0000168 AC XY: 12 AN XY: 714442

African (AFR) AF: 0.00 AC: 0 AN: 33044

American (AMR) AF: 0.000494 AC: 22 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25916

East Asian (EAS) AF: 0.00 AC: 0 AN: 39252

South Asian (SAS) AF: 0.00 AC: 0 AN: 85412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1087848

Other (OTH) AF: 0.0000169 AC: 1 AN: 59282

GnomAD4 genome AF: 0.000225 AC: 34 AN: 151028 Hom.: 2 Cov.: 30 AF XY: 0.000326 AC XY: 24 AN XY: 73656

African (AFR) AF: 0.00 AC: 0 AN: 41060

American (AMR) AF: 0.00218 AC: 33 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67706

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000212

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Bardet-Biedl syndrome 9 (3)
1	-	-	Bardet-Biedl syndrome (1)
1	-	-	BBS9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs747388658; hg19: chr7-33195293;