rs28622379

Variant names:

• chr7-33367761-T-C
• rs28622379
• NM_198428.3:c.1694-6T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-33367761-T-C
• chr7-33367761-T-G

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.1694-6T>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 0.00508 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, intron
• Scores: Splicing: ADA: 0.00001122
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.788
• Publications: 3 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=-0.84).
• BP6: Variant 7-33367761-T-C is Benign according to our data. Variant chr7-33367761-T-C is described in ClinVar as Benign. ClinVar VariationId is 263121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198428.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	NM_198428.3	MANE Select	c.1694-6T>C		splice_region intron	N/A	NP_940820.1
	BBS9	NM_001348041.4		c.1694-6T>C		splice_region intron	N/A	NP_001334970.1
	BBS9	NM_001348036.1		c.1694-6T>C		splice_region intron	N/A	NP_001334965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	ENST00000242067.11	TSL:1 MANE Select	c.1694-6T>C		splice_region intron	N/A	ENSP00000242067.6
	BBS9	ENST00000434373.3	TSL:1	c.392-6T>C		splice_region intron	N/A	ENSP00000388114.1
	BBS9	ENST00000433714.5	TSL:1	n.*455-6T>C		splice_region intron	N/A	ENSP00000412159.1

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

GnomAD2 exomes AF: 0.00905 AC: 2275 AN: 251336 AF XY: 0.0109

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 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

African (AFR) AF: 0.0225 AC: 753 AN: 33458

American (AMR) AF: 0.00197 AC: 88 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 472 AN: 26118

East Asian (EAS) AF: 0.00333 AC: 132 AN: 39614

South Asian (SAS) AF: 0.0455 AC: 3928 AN: 86244

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53406

Middle Eastern (MID) AF: 0.0243 AC: 140 AN: 5764

European-Non Finnish (NFE) AF: 0.000825 AC: 917 AN: 1111386

Other (OTH) AF: 0.00767 AC: 463 AN: 60356

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

African (AFR) AF: 0.0204 AC: 848 AN: 41572

American (AMR) AF: 0.00248 AC: 38 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3468

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5184

South Asian (SAS) AF: 0.0456 AC: 220 AN: 4822

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 67996

Other (OTH) AF: 0.00945 AC: 20 AN: 2116

Alfa AF: 0.00358 Hom.: 3

Bravo AF: 0.00794

Asia WGS AF: 0.0260 AC: 89 AN: 3474

EpiCase AF: 0.00251

EpiControl AF: 0.00255

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	Bardet-Biedl syndrome 9 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.1
DANN	Benign	0.58
PhyloP100		0.79
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28622379; hg19: chr7-33407373;