15-72686211-C-T

Variant names:

• chr15-72686211-C-T
• rs56368716
• NM_033028.5:c.-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.-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:6
• Conservation: PhyloP100: -0.640
• Publications: 6 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]

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

Our verdict: Benign. The variant received -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 VariationId is 193472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.089 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	NM_033028.5	MANE Select	c.-17C>T		5_prime_UTR	Exon 1 of 16	NP_149017.2
	BBS4	NR_045565.2		n.5C>T		non_coding_transcript_exon	Exon 1 of 17
	BBS4	NR_045566.2		n.5C>T		non_coding_transcript_exon	Exon 1 of 16

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.-17C>T		5_prime_UTR	Exon 1 of 16	ENSP00000268057.4
	BBS4	ENST00000566400.6	TSL:1	c.-486C>T		5_prime_UTR	Exon 1 of 15	ENSP00000456759.2
	BBS4	ENST00000561914.6	TSL:5	n.-17C>T		non_coding_transcript_exon	Exon 1 of 15	ENSP00000457795.1

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

GnomAD2 exomes AF: 0.0682 AC: 11423 AN: 167538 AF XY: 0.0672

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 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

African (AFR) AF: 0.0130 AC: 417 AN: 32128

American (AMR) AF: 0.0551 AC: 2040 AN: 37002

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3184 AN: 25248

East Asian (EAS) AF: 0.000546 AC: 20 AN: 36618

South Asian (SAS) AF: 0.0219 AC: 1747 AN: 79696

European-Finnish (FIN) AF: 0.135 AC: 6570 AN: 48604

Middle Eastern (MID) AF: 0.0860 AC: 367 AN: 4268

European-Non Finnish (NFE) AF: 0.0811 AC: 87875 AN: 1084004

Other (OTH) AF: 0.0718 AC: 4180 AN: 58208

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

African (AFR) AF: 0.0133 AC: 551 AN: 41584

American (AMR) AF: 0.0755 AC: 1156 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.0176 AC: 85 AN: 4826

European-Finnish (FIN) AF: 0.142 AC: 1511 AN: 10614

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0909 AC: 6180 AN: 68004

Other (OTH) AF: 0.0776 AC: 164 AN: 2114

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 12, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Bardet-Biedl syndrome 4 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.3
DANN	Benign	0.90
PhyloP100		-0.64
PromoterAI		0.047	Neutral
Mutation Taster		=294/6	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: rs56368716; hg19: chr15-72978552;