rs11637927

chr15-72686190-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000395205.6(BBS4):c.-507C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0662 in 1,549,504 control chromosomes in the GnomAD database, including 3,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (239 hom., cov: 32)
  • Exomes 𝑓: 0.068 (3734 hom.)
• Consequence: BBS4 ENST00000395205.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.77

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]

HIGD2B (HGNC:26984): (HIG1 hypoxia inducible domain family member 2B) Predicted to be involved in mitochondrial respirasome assembly. Predicted to be integral component of membrane. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 15-72686190-C-A is Benign according to our data. Variant chr15-72686190-C-A is described in ClinVar as [Benign]. Clinvar id is 262133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72686190-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HIGD2B	NM_001350932.3			upstream_gene_variant		ENST00000311755.6
BBS4	NM_033028.5			upstream_gene_variant		ENST00000268057.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS4	ENST00000268057.9			upstream_gene_variant		1	NM_033028.5	P1
HIGD2B	ENST00000311755.6			upstream_gene_variant		1	NM_001350932.3	P1

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7164 AN: 152216 Hom.: 239 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0634

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0729

Gnomad OTH AF: 0.0488

GnomAD3 exomes AF: 0.0458 AC: 7214 AN: 157460 Hom.: 249 AF XY: 0.0453 AC XY: 3786 AN XY: 83536

Gnomad AFR exome AF: 0.00973

Gnomad AMR exome AF: 0.0352

Gnomad ASJ exome AF: 0.0235

Gnomad EAS exome AF: 0.0000851

Gnomad SAS exome AF: 0.0215

Gnomad FIN exome AF: 0.0606

Gnomad NFE exome AF: 0.0725

Gnomad OTH exome AF: 0.0465

GnomAD4 exome AF: 0.0683 AC: 95471 AN: 1397170 Hom.: 3734 Cov.: 30 AF XY: 0.0672 AC XY: 46327 AN XY: 689498

Gnomad4 AFR exome AF: 0.00979

Gnomad4 AMR exome AF: 0.0360

Gnomad4 ASJ exome AF: 0.0215

Gnomad4 EAS exome AF: 0.000111

Gnomad4 SAS exome AF: 0.0217

Gnomad4 FIN exome AF: 0.0584

Gnomad4 NFE exome AF: 0.0794

Gnomad4 OTH exome AF: 0.0542

GnomAD4 genome AF: 0.0470 AC: 7163 AN: 152334 Hom.: 239 Cov.: 32 AF XY: 0.0453 AC XY: 3378 AN XY: 74500

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.0375

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0211

Gnomad4 FIN AF: 0.0634

Gnomad4 NFE AF: 0.0729

Gnomad4 OTH AF: 0.0478

Alfa AF: 0.0647 Hom.: 446

Bravo AF: 0.0438

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Bardet-Biedl syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.030
Dann	Benign	0.86

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: rs11637927; hg19: chr15-72978531;