rs150754122

Positions:

• chr15-72731288-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000268057.9(BBS4):​c.712-17C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,960 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (14 hom., cov: 29)
  • Exomes 𝑓: 0.015 (187 hom.)
• Consequence: BBS4 ENST00000268057.9 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.50

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 15-72731288-C-G is Benign according to our data. Variant chr15-72731288-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 262141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0103 (1562/152130) while in subpopulation NFE AF= 0.0168 (1143/67974). AF 95% confidence interval is 0.016. There are 14 homozygotes in gnomad4. There are 678 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS4	NM_033028.5	c.712-17C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000268057.9	NP_149017.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS4	ENST00000268057.9	c.712-17C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_033028.5	ENSP00000268057	P1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1561 AN: 152012 Hom.: 14 Cov.: 29

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.00473

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00963 AC: 2422 AN: 251454 Hom.: 19 AF XY: 0.00937 AC XY: 1273 AN XY: 135910

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00287

Gnomad FIN exome AF: 0.00411

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.0148 AC: 21610 AN: 1461830 Hom.: 187 Cov.: 31 AF XY: 0.0145 AC XY: 10512 AN XY: 727234

Gnomad4 AFR exome AF: 0.00224

Gnomad4 AMR exome AF: 0.00657

Gnomad4 ASJ exome AF: 0.0139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00357

Gnomad4 FIN exome AF: 0.00431

Gnomad4 NFE exome AF: 0.0175

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.0103 AC: 1562 AN: 152130 Hom.: 14 Cov.: 29 AF XY: 0.00912 AC XY: 678 AN XY: 74368

Gnomad4 AFR AF: 0.00272

Gnomad4 AMR AF: 0.00935

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00473

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0138 Hom.: 1

Bravo AF: 0.0105

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Bardet-Biedl syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0070
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs150754122; hg19: chr15-73023629;