chr7-33505563-C-T

Variant names:

• chr7-33505563-C-T
• rs116483694
• NM_198428.3:c.2216C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BS1 BS2_Supporting

The NM_198428.3(BBS9):​c.2216C>T​(p.Ala739Val) variant causes a missense change. The variant allele was found at a frequency of 0.000566 in 1,614,118 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A739T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: BBS9 NM_198428.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.73
• Publications: 4 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0073854923).
• BP6: Variant 7-33505563-C-T is Benign according to our data. Variant chr7-33505563-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00273 (416/152344) while in subpopulation AFR AF = 0.0095 (395/41584). AF 95% confidence interval is 0.00873. There are 2 homozygotes in GnomAd4. There are 182 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• 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_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.2216C>T	p.Ala739Val	missense	Exon 20 of 23	NP_940820.1	Q3SYG4-1
	BBS9	NM_001348041.4		c.2216C>T	p.Ala739Val	missense	Exon 20 of 23	NP_001334970.1	A0A5F9ZH14
	BBS9	NM_001348036.1		c.2216C>T	p.Ala739Val	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.2216C>T	p.Ala739Val	missense	Exon 20 of 23	ENSP00000242067.6	Q3SYG4-1
	BBS9	ENST00000434373.3	TSL:1	c.914C>T	p.Ala305Val	missense	Exon 9 of 11	ENSP00000388114.1	H7BZ69
	BBS9	ENST00000433714.5	TSL:1	n.*977C>T		non_coding_transcript_exon	Exon 21 of 24	ENSP00000412159.1	F8WCG5

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152226 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00945

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000773 AC: 194 AN: 250868 AF XY: 0.000539

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000341 AC: 498 AN: 1461774 Hom.: 1 Cov.: 31 AF XY: 0.000292 AC XY: 212 AN XY: 727186

African (AFR) AF: 0.0104 AC: 348 AN: 33462

American (AMR) AF: 0.000514 AC: 23 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5746

European-Non Finnish (NFE) AF: 0.0000782 AC: 87 AN: 1111958

Other (OTH) AF: 0.000530 AC: 32 AN: 60386

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152344 Hom.: 2 Cov.: 33 AF XY: 0.00244 AC XY: 182 AN XY: 74494

African (AFR) AF: 0.00950 AC: 395 AN: 41584

American (AMR) AF: 0.000719 AC: 11 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00102 Hom.: 1

Bravo AF: 0.00322

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000955 AC: 116

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Bardet-Biedl syndrome 1 (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	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.067
Sift	Benign	0.076	T
Sift4G	Benign	0.16	T
Polyphen		0.29	B
Vest4		0.25
MVP		0.33
MPC		0.063
ClinPred		0.012	T
GERP RS		4.9
Varity_R		0.13
gMVP		0.25
Mutation Taster		=99/1	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: rs116483694; hg19: chr7-33545175;