chr15-72686245-C-T

Variant names:

• chr15-72686245-C-T
• rs113994187
• ENST00000395205.7:c.-447C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001252678.2(BBS4):​c.-452C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,413,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: BBS4 NM_001252678.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -4.88
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 15-72686245-C-T is Benign according to our data. Variant chr15-72686245-C-T is described in ClinVar as Benign. ClinVar VariationId is 21737.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001252678.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	NM_033028.5	MANE Select	c.18C>T	p.Val6Val	synonymous	Exon 1 of 16	NP_149017.2
	BBS4	NM_001252678.2		c.-452C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001239607.1	Q96RK4-3
	BBS4	NM_001320665.2		c.18C>T	p.Val6Val	synonymous	Exon 1 of 15	NP_001307594.1	H3BSL2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000395205.7	TSL:1	c.-447C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000378631.3	Q96RK4-3
	BBS4	ENST00000566400.6	TSL:1	c.-452C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000456759.2	H3BSL3
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.18C>T	p.Val6Val	synonymous	Exon 1 of 16	ENSP00000268057.4	Q96RK4-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000567 AC: 1 AN: 176356 AF XY: 0.0000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000136

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000637 AC: 9 AN: 1413270 Hom.: 0 Cov.: 31 AF XY: 0.00000859 AC XY: 6 AN XY: 698478

African (AFR) AF: 0.0000310 AC: 1 AN: 32310

American (AMR) AF: 0.00 AC: 0 AN: 37928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25318

East Asian (EAS) AF: 0.00 AC: 0 AN: 37022

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4766

European-Non Finnish (NFE) AF: 0.00000643 AC: 7 AN: 1087964

Other (OTH) AF: 0.00 AC: 0 AN: 58462

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.4
DANN	Benign	0.93
PhyloP100		-4.9
PromoterAI		-0.038	Neutral

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: rs113994187; hg19: chr15-72978586;