rs75847960

Variant names:

• chr15-72737433-T-C
• rs75847960
• NM_033028.5:c.1451-45T>C

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.1451-45T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,501,516 control chromosomes in the GnomAD database, including 10,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (668 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9425 hom.)
• Consequence: BBS4 NM_033028.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.127
• Publications: 4 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
• 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=-0.74).
• BP6: Variant 15-72737433-T-C is Benign according to our data. Variant chr15-72737433-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 21732.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS4	NM_033028.5	c.1451-45T>C		intron_variant	Intron 15 of 15	ENST00000268057.9	NP_149017.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS4	ENST00000268057.9	c.1451-45T>C		intron_variant	Intron 15 of 15	1	NM_033028.5	ENSP00000268057.4

Frequencies

GnomAD3 genomes AF: 0.0849 AC: 12916 AN: 152142 Hom.: 668 Cov.: 32

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0611

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0820

Gnomad FIN AF: 0.0603

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0861

GnomAD2 exomes AF: 0.0813 AC: 16024 AN: 196986 AF XY: 0.0842

Gnomad AFR exome AF: 0.0505

Gnomad AMR exome AF: 0.0488

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.000258

Gnomad FIN exome AF: 0.0547

Gnomad NFE exome AF: 0.115

Gnomad OTH exome AF: 0.0815

GnomAD4 exome AF: 0.113 AC: 152567 AN: 1349256 Hom.: 9425 Cov.: 20 AF XY: 0.112 AC XY: 75334 AN XY: 671982

African (AFR) AF: 0.0533 AC: 1662 AN: 31204

American (AMR) AF: 0.0506 AC: 2011 AN: 39758

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 2632 AN: 24874

East Asian (EAS) AF: 0.000157 AC: 6 AN: 38318

South Asian (SAS) AF: 0.0897 AC: 7148 AN: 79708

European-Finnish (FIN) AF: 0.0549 AC: 2805 AN: 51088

Middle Eastern (MID) AF: 0.0902 AC: 502 AN: 5564

European-Non Finnish (NFE) AF: 0.127 AC: 129733 AN: 1022254

Other (OTH) AF: 0.107 AC: 6068 AN: 56488

GnomAD4 genome AF: 0.0849 AC: 12924 AN: 152260 Hom.: 668 Cov.: 32 AF XY: 0.0810 AC XY: 6027 AN XY: 74452

African (AFR) AF: 0.0541 AC: 2247 AN: 41556

American (AMR) AF: 0.0610 AC: 933 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 380 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0810 AC: 391 AN: 4826

European-Finnish (FIN) AF: 0.0603 AC: 640 AN: 10612

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8026 AN: 68006

Other (OTH) AF: 0.0852 AC: 180 AN: 2112

Alfa AF: 0.0977 Hom.: 126

Bravo AF: 0.0830

Asia WGS AF: 0.0360 AC: 124 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Bardet-Biedl syndrome Benign:1

Oct 13, 2009

GeneReviews

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	14
DANN	Benign	0.87
PhyloP100		0.13
Mutation Taster		=100/0	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: rs75847960; hg19: chr15-73029774;