15-72686237-G-T

Variant names:

• chr15-72686237-G-T
• rs1336636537
• NM_033028.5:c.10G>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033028.5(BBS4):​c.10G>T​(p.Glu4*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BBS4 NM_033028.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.87

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-72686237-G-T is Pathogenic according to our data. Variant chr15-72686237-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2197130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72686237-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS4	NM_033028.5	c.10G>T	p.Glu4*	stop_gained	Exon 1 of 16	ENST00000268057.9	NP_149017.2
HIGD2B	NM_001350932.3	c.-612C>A		upstream_gene_variant		ENST00000311755.6	NP_001337861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS4	ENST00000268057.9	c.10G>T	p.Glu4*	stop_gained	Exon 1 of 16	1	NM_033028.5	ENSP00000268057.4
HIGD2B	ENST00000311755.6	c.-612C>A		upstream_gene_variant		1	NM_001350932.3	ENSP00000307951.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1413710 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 698724

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bardet-Biedl syndrome 4 Pathogenic:2

Aug 10, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bardet-Biedl syndrome Pathogenic:1

Aug 30, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu4*) in the BBS4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BBS4 are known to be pathogenic (PMID: 11381270, 12016587, 20177705, 27894351). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BBS4-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	49
DANN	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.50	D
Vest4		0.70
GERP RS		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1336636537; hg19: chr15-72978578;