rs113994184

Variant names:

• chr15-72695178-G-GA
• rs113994184
• NM_033028.5:c.28dupA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PVS1 PM2 BP6

The NM_033028.5(BBS4):​c.28dupA​(p.Thr10AsnfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Benign (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS4 NM_033028.5 frameshift
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.97
• 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]

BBS4 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 4

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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 109 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 15-72695178-G-GA is Benign according to our data. Variant chr15-72695178-G-GA is described in ClinVar as Benign. ClinVar VariationId is 21739.Status of the report is no_assertion_criteria_provided, 0 stars.

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.28dupA	p.Thr10AsnfsTer8	frameshift	Exon 2 of 16	NP_149017.2
	BBS4	NM_001320665.2		c.28dupA	p.Thr10AsnfsTer8	frameshift	Exon 2 of 15	NP_001307594.1	H3BSL2
	BBS4	NM_001252678.2		c.-446+8929dupA		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.28dupA	p.Thr10AsnfsTer8	frameshift	Exon 2 of 16	ENSP00000268057.4	Q96RK4-1
	BBS4	ENST00000395205.7	TSL:1	c.-441+8929dupA		intron	N/A	ENSP00000378631.3	Q96RK4-3
	BBS4	ENST00000566400.6	TSL:1	c.-446+8929dupA		intron	N/A	ENSP00000456759.2	H3BSL3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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
PhyloP100		2.0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs113994184;

hg19: chr15-72987519;