rs140882212

Variant names:

• chr7-33505641-A-G
• rs140882212
• NM_198428.3:c.2294A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_198428.3(BBS9):​c.2294A>G​(p.Glu765Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000849 in 1,613,334 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (2 hom.)
• Consequence: BBS9 NM_198428.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.37
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• BBS9-related ciliopathy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07640228).
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	NM_198428.3	MANE Select	c.2294A>G	p.Glu765Gly	missense	Exon 20 of 23	NP_940820.1	Q3SYG4-1
	BBS9	NM_001348041.4		c.2294A>G	p.Glu765Gly	missense	Exon 20 of 23	NP_001334970.1	A0A5F9ZH14
	BBS9	NM_001348036.1		c.2294A>G	p.Glu765Gly	missense	Exon 20 of 23	NP_001334965.1	Q3SYG4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	ENST00000242067.11	TSL:1 MANE Select	c.2294A>G	p.Glu765Gly	missense	Exon 20 of 23	ENSP00000242067.6	Q3SYG4-1
	BBS9	ENST00000434373.3	TSL:1	c.992A>G	p.Glu331Gly	missense	Exon 9 of 11	ENSP00000388114.1	H7BZ69
	BBS9	ENST00000433714.5	TSL:1	n.*1055A>G		non_coding_transcript_exon	Exon 21 of 24	ENSP00000412159.1	F8WCG5

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000838 AC: 21 AN: 250522 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1460978 Hom.: 2 Cov.: 31 AF XY: 0.0000482 AC XY: 35 AN XY: 726812

African (AFR) AF: 0.00155 AC: 52 AN: 33446

American (AMR) AF: 0.0000671 AC: 3 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.000377 AC: 2 AN: 5306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111870

Other (OTH) AF: 0.000381 AC: 23 AN: 60308

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74516

African (AFR) AF: 0.00127 AC: 53 AN: 41584

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Bardet-Biedl syndrome (1)
-	1	-	Bardet-Biedl syndrome 9 (1)
-	1	-	BBS9-related disorder (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.4
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.17
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.020	D
Polyphen		0.92	P
Vest4		0.55
MVP		0.56
MPC		0.37
ClinPred		0.083	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.27
Mutation Taster		=64/36	polymorphism

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: rs140882212; hg19: chr7-33545253;