rs11773504

Variant names:

• chr7-33349101-G-A
• rs11773504
• NM_198428.3:c.1363G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198428.3(BBS9):​c.1363G>A​(p.Ala455Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,610,110 control chromosomes in the GnomAD database, including 34,089 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2564 hom., cov: 32)
  • Exomes 𝑓: 0.21 (31525 hom.)
• Consequence: BBS9 NM_198428.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.38
• Publications: 29 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.8375807E-4).
• BP6: Variant 7-33349101-G-A is Benign according to our data. Variant chr7-33349101-G-A is described in ClinVar as Benign. ClinVar VariationId is 263117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

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.1363G>A	p.Ala455Thr	missense	Exon 13 of 23	NP_940820.1	Q3SYG4-1
	BBS9	NM_001348041.4		c.1363G>A	p.Ala455Thr	missense	Exon 13 of 23	NP_001334970.1	A0A5F9ZH14
	BBS9	NM_001348036.1		c.1363G>A	p.Ala455Thr	missense	Exon 13 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.1363G>A	p.Ala455Thr	missense	Exon 13 of 23	ENSP00000242067.6	Q3SYG4-1
	BBS9	ENST00000434373.3	TSL:1	c.61G>A	p.Ala21Thr	missense	Exon 2 of 11	ENSP00000388114.1	H7BZ69
	BBS9	ENST00000433714.5	TSL:1	n.*124G>A		non_coding_transcript_exon	Exon 14 of 24	ENSP00000412159.1	F8WCG5

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26979 AN: 152020 Hom.: 2562 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.182

GnomAD2 exomes AF: 0.205 AC: 51549 AN: 251226 AF XY: 0.207

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.186

Gnomad EAS exome AF: 0.210

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.205 AC: 298906 AN: 1457972 Hom.: 31525 Cov.: 32 AF XY: 0.206 AC XY: 149616 AN XY: 725512

African (AFR) AF: 0.112 AC: 3759 AN: 33422

American (AMR) AF: 0.215 AC: 9631 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4661 AN: 26092

East Asian (EAS) AF: 0.171 AC: 6777 AN: 39580

South Asian (SAS) AF: 0.230 AC: 19860 AN: 86166

European-Finnish (FIN) AF: 0.213 AC: 11338 AN: 53248

Middle Eastern (MID) AF: 0.165 AC: 949 AN: 5756

European-Non Finnish (NFE) AF: 0.207 AC: 229811 AN: 1108750

Other (OTH) AF: 0.201 AC: 12120 AN: 60254

GnomAD4 genome AF: 0.177 AC: 26997 AN: 152138 Hom.: 2564 Cov.: 32 AF XY: 0.177 AC XY: 13187 AN XY: 74366

African (AFR) AF: 0.117 AC: 4877 AN: 41512

American (AMR) AF: 0.185 AC: 2825 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 621 AN: 3472

East Asian (EAS) AF: 0.197 AC: 1020 AN: 5184

South Asian (SAS) AF: 0.205 AC: 991 AN: 4826

European-Finnish (FIN) AF: 0.211 AC: 2227 AN: 10550

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13913 AN: 67998

Other (OTH) AF: 0.185 AC: 391 AN: 2116

Alfa AF: 0.181 Hom.: 2024

Bravo AF: 0.173

TwinsUK AF: 0.219 AC: 811

ALSPAC AF: 0.214 AC: 823

ESP6500AA AF: 0.126 AC: 556

ESP6500EA AF: 0.201 AC: 1727

ExAC AF: 0.204 AC: 24791

Asia WGS AF: 0.203 AC: 708 AN: 3478

EpiCase AF: 0.203

EpiControl AF: 0.198

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Bardet-Biedl syndrome 1 (2)
-	-	2	not specified (2)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	Bardet-Biedl syndrome 9 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.00088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.4
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.045
Sift	Benign	0.23	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.066
MPC		0.097
ClinPred		0.0075	T
GERP RS		3.2
Varity_R		0.091
gMVP		0.19
Mutation Taster		=100/0	polymorphism (auto)

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: rs11773504; hg19: chr7-33388713; COSMIC: COSV54160898; COSMIC: COSV54160898;