15-72686190-C-A

Variant names:

• chr15-72686190-C-A
• rs11637927
• ENST00000566400.6:c.-507C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000566400.6(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 ENST00000566400.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.77
• Publications: 19 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=-0.81).
• BP6: Variant 15-72686190-C-A is Benign according to our data. Variant chr15-72686190-C-A is described in ClinVar as Benign. ClinVar VariationId is 262133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0712 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000566400.6. 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.-38C>A		upstream_gene	N/A	NP_149017.2
	HIGD2B	NM_001350932.3	MANE Select	c.-565G>T		upstream_gene	N/A	NP_001337861.1	Q4VC39
	BBS4	NM_001320665.2		c.-38C>A		upstream_gene	N/A	NP_001307594.1	H3BSL2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000566400.6	TSL:1	c.-507C>A		5_prime_UTR	Exon 1 of 15	ENSP00000456759.2	H3BSL3
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.-38C>A		upstream_gene	N/A	ENSP00000268057.4	Q96RK4-1
	HIGD2B	ENST00000311755.6	TSL:1 MANE Select	c.-565G>T		upstream_gene	N/A	ENSP00000307951.3	Q4VC39

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

GnomAD2 exomes AF: 0.0458 AC: 7214 AN: 157460 AF XY: 0.0453

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 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

African (AFR) AF: 0.00979 AC: 311 AN: 31762

American (AMR) AF: 0.0360 AC: 1295 AN: 36016

Ashkenazi Jewish (ASJ) AF: 0.0215 AC: 543 AN: 25202

East Asian (EAS) AF: 0.000111 AC: 4 AN: 36054

South Asian (SAS) AF: 0.0217 AC: 1718 AN: 79276

European-Finnish (FIN) AF: 0.0584 AC: 2767 AN: 47354

Middle Eastern (MID) AF: 0.00773 AC: 32 AN: 4142

European-Non Finnish (NFE) AF: 0.0794 AC: 85665 AN: 1079472

Other (OTH) AF: 0.0542 AC: 3136 AN: 57892

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

African (AFR) AF: 0.0144 AC: 599 AN: 41584

American (AMR) AF: 0.0375 AC: 573 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0211 AC: 102 AN: 4830

European-Finnish (FIN) AF: 0.0634 AC: 674 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0729 AC: 4956 AN: 68020

Other (OTH) AF: 0.0478 AC: 101 AN: 2114

Alfa AF: 0.0646 Hom.: 532

Bravo AF: 0.0438

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bardet-Biedl syndrome 4 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.030
DANN	Benign	0.86
PhyloP100		-2.8
PromoterAI		0.30	Neutral
Mutation Taster		=300/0	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: rs11637927; hg19: chr15-72978531;