15-72709694-G-A

Variant names:

• chr15-72709694-G-A
• rs8033604
• NM_033028.5:c.77-6G>A

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.77-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,604,748 control chromosomes in the GnomAD database, including 788,343 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68974 hom., cov: 31)
  • Exomes 𝑓: 0.99 (719369 hom.)
• Consequence: BBS4 NM_033028.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001418
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.47
• Publications: 15 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]

BBS4 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• BBS4-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-72709694-G-A is Benign according to our data. Variant chr15-72709694-G-A is described in ClinVar as Benign. ClinVar VariationId is 262143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	NM_033028.5	MANE Select	c.77-6G>A		splice_region intron	N/A	NP_149017.2
	BBS4	NM_001320665.2		c.77-6G>A		splice_region intron	N/A	NP_001307594.1	H3BSL2
	BBS4	NM_001252678.2		c.-445-6G>A		splice_region intron	N/A	NP_001239607.1	Q96RK4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.77-6G>A		splice_region intron	N/A	ENSP00000268057.4	Q96RK4-1
	BBS4	ENST00000395205.7	TSL:1	c.-440-6G>A		splice_region intron	N/A	ENSP00000378631.3	Q96RK4-3
	BBS4	ENST00000566400.6	TSL:1	c.-445-6G>A		splice_region intron	N/A	ENSP00000456759.2	H3BSL3

Frequencies

GnomAD3 genomes AF: 0.949 AC: 144274 AN: 152040 Hom.: 68941 Cov.: 31

Gnomad AFR AF: 0.821

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.967

GnomAD2 exomes AF: 0.986 AC: 247902 AN: 251318 AF XY: 0.991

Gnomad AFR exome AF: 0.813

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.995 AC: 1445076 AN: 1452590 Hom.: 719369 Cov.: 31 AF XY: 0.996 AC XY: 720127 AN XY: 723278

African (AFR) AF: 0.817 AC: 27216 AN: 33296

American (AMR) AF: 0.991 AC: 44301 AN: 44710

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26084 AN: 26084

East Asian (EAS) AF: 1.00 AC: 39628 AN: 39628

South Asian (SAS) AF: 1.00 AC: 86010 AN: 86040

European-Finnish (FIN) AF: 1.00 AC: 53208 AN: 53210

Middle Eastern (MID) AF: 0.990 AC: 5703 AN: 5758

European-Non Finnish (NFE) AF: 1.00 AC: 1103463 AN: 1103748

Other (OTH) AF: 0.989 AC: 59463 AN: 60116

GnomAD4 genome AF: 0.949 AC: 144358 AN: 152158 Hom.: 68974 Cov.: 31 AF XY: 0.951 AC XY: 70754 AN XY: 74412

African (AFR) AF: 0.820 AC: 33989 AN: 41432

American (AMR) AF: 0.984 AC: 15044 AN: 15288

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5192 AN: 5192

South Asian (SAS) AF: 1.00 AC: 4816 AN: 4818

European-Finnish (FIN) AF: 1.00 AC: 10610 AN: 10610

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67988 AN: 68028

Other (OTH) AF: 0.968 AC: 2044 AN: 2112

Alfa AF: 0.981 Hom.: 241362

Bravo AF: 0.941

Asia WGS AF: 0.989 AC: 3441 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 0.999

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Bardet-Biedl syndrome (2)
-	-	2	Bardet-Biedl syndrome 4 (2)
-	-	2	not specified (2)
-	-	1	Bardet-Biedl syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.54
DANN	Benign	0.73
PhyloP100		-1.5
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0080
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: rs8033604; hg19: chr15-73002035;