15-72686211-C-T

Variant summary

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

The NM_033028.5(BBS4):c.-17C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0748 in 1,558,082 control chromosomes in the GnomAD database, including 5,064 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (525 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4539 hom.)
• Consequence: BBS4 NM_033028.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.640

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=-0.78).
• BP6: Variant 15-72686211-C-T is Benign according to our data. Variant chr15-72686211-C-T is described in ClinVar as [Benign]. Clinvar id is 193472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72686211-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.089 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS4	NM_033028.5	c.-17C>T		5_prime_UTR_variant	1/16	ENST00000268057.9
HIGD2B	NM_001350932.3			upstream_gene_variant		ENST00000311755.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS4	ENST00000268057.9	c.-17C>T		5_prime_UTR_variant	1/16	1	NM_033028.5	P1
HIGD2B	ENST00000311755.6			upstream_gene_variant		1	NM_001350932.3	P1

Frequencies

GnomAD3 genomes AF: 0.0668 AC: 10164 AN: 152188 Hom.: 525 Cov.: 32

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0756

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0908

Gnomad OTH AF: 0.0784

GnomAD3 exomes AF: 0.0682 AC: 11423 AN: 167538 Hom.: 585 AF XY: 0.0672 AC XY: 5982 AN XY: 88998

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0528

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000319

Gnomad SAS exome AF: 0.0211

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.0867

Gnomad OTH exome AF: 0.0785

GnomAD4 exome AF: 0.0757 AC: 106400 AN: 1405776 Hom.: 4539 Cov.: 31 AF XY: 0.0747 AC XY: 51835 AN XY: 694240

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.0551

Gnomad4 ASJ exome AF: 0.126

Gnomad4 EAS exome AF: 0.000546

Gnomad4 SAS exome AF: 0.0219

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.0811

Gnomad4 OTH exome AF: 0.0718

GnomAD4 genome AF: 0.0667 AC: 10160 AN: 152306 Hom.: 525 Cov.: 32 AF XY: 0.0694 AC XY: 5168 AN XY: 74474

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.0755

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.0909

Gnomad4 OTH AF: 0.0776

Alfa AF: 0.0894 Hom.: 141

Bravo AF: 0.0588

Asia WGS AF: 0.0120 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Bardet-Biedl syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.78
Cadd	Benign	7.3
Dann	Benign	0.90

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: rs56368716; hg19: chr15-72978552;