rs80334351

Variant names:

• chr15-72716867-C-T
• rs80334351
• NM_033028.5:c.405+17C>T

Variant summary

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

The NM_033028.5(BBS4):​c.405+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,570,000 control chromosomes in the GnomAD database, including 1,090 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (104 hom., cov: 32)
  • Exomes 𝑓: 0.030 (986 hom.)
• Consequence: BBS4 NM_033028.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.171
• Publications: 2 publications found

Genes affected

BBS4 (HGNC:969): (Bardet-Biedl syndrome 4) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse. The similar phenotypes exhibited by mutations in BBS gene family members are likely due to the protein's shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene has sequence similarity to O-linked N-acetylglucosamine (O-GlcNAc) transferases in plants and archaebacteria and in human forms a multi-protein "BBSome" complex with seven other BBS proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

BBS4 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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=-0.61).
• BP6: Variant 15-72716867-C-T is Benign according to our data. Variant chr15-72716867-C-T is described in ClinVar as Benign. ClinVar VariationId is 262139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0697 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033028.5. 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
	BBS4	NM_033028.5	MANE Select	c.405+17C>T		intron	N/A	NP_149017.2
	BBS4	NM_001320665.2		c.405+17C>T		intron	N/A	NP_001307594.1
	BBS4	NM_001252678.2		c.-117+17C>T		intron	N/A	NP_001239607.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.405+17C>T		intron	N/A	ENSP00000268057.4
	BBS4	ENST00000395205.7	TSL:1	c.-112+17C>T		intron	N/A	ENSP00000378631.3
	BBS4	ENST00000566400.6	TSL:1	c.-117+17C>T		intron	N/A	ENSP00000456759.2

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3909 AN: 152188 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.00511

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0733

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0437 AC: 10459 AN: 239186 AF XY: 0.0406

Gnomad AFR exome AF: 0.00568

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0360

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0425

GnomAD4 exome AF: 0.0296 AC: 41897 AN: 1417694 Hom.: 986 Cov.: 25 AF XY: 0.0295 AC XY: 20874 AN XY: 706524

African (AFR) AF: 0.00524 AC: 171 AN: 32626

American (AMR) AF: 0.135 AC: 5916 AN: 43924

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 810 AN: 25448

East Asian (EAS) AF: 0.000786 AC: 31 AN: 39452

South Asian (SAS) AF: 0.0398 AC: 3355 AN: 84346

European-Finnish (FIN) AF: 0.0367 AC: 1939 AN: 52898

Middle Eastern (MID) AF: 0.0382 AC: 198 AN: 5188

European-Non Finnish (NFE) AF: 0.0260 AC: 27929 AN: 1075082

Other (OTH) AF: 0.0264 AC: 1548 AN: 58730

GnomAD4 genome AF: 0.0256 AC: 3906 AN: 152306 Hom.: 104 Cov.: 32 AF XY: 0.0271 AC XY: 2020 AN XY: 74460

African (AFR) AF: 0.00510 AC: 212 AN: 41574

American (AMR) AF: 0.0733 AC: 1120 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5192

South Asian (SAS) AF: 0.0315 AC: 152 AN: 4818

European-Finnish (FIN) AF: 0.0340 AC: 361 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0272 AC: 1848 AN: 68034

Other (OTH) AF: 0.0284 AC: 60 AN: 2114

Alfa AF: 0.0279 Hom.: 100

Bravo AF: 0.0292

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.77
PhyloP100		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs80334351; hg19: chr15-73009208;