NM_033028.5:c.1311_1312insT

Variant names:

• chr15-72736824-C-CT
• rs1555502637
• NM_033028.5:c.1311_1312insT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_033028.5(BBS4):​c.1311_1312insT​(p.Lys438fs) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS4 NM_033028.5 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.20
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-72736824-C-CT is Pathogenic according to our data. Variant chr15-72736824-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 1324345.Status of the report is criteria_provided_single_submitter, 1 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.1311_1312insT	p.Lys438fs	frameshift stop_gained	Exon 15 of 16	NP_149017.2
	BBS4	NM_001320665.2		c.1242_1243insT	p.Lys415fs	frameshift stop_gained	Exon 14 of 15	NP_001307594.1
	BBS4	NM_001252678.2		c.795_796insT	p.Lys266fs	frameshift stop_gained	Exon 14 of 15	NP_001239607.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.1311_1312insT	p.Lys438fs	frameshift stop_gained	Exon 15 of 16	ENSP00000268057.4
	BBS4	ENST00000395205.7	TSL:1	c.795_796insT	p.Lys266fs	frameshift stop_gained	Exon 14 of 15	ENSP00000378631.3
	BBS4	ENST00000566400.6	TSL:1	c.795_796insT	p.Lys266fs	frameshift stop_gained	Exon 14 of 15	ENSP00000456759.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Bardet-Biedl syndrome 4 (1)
1	-	-	BBS4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=0/200	disease causing (fs/PTC)

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: rs1555502637; hg19: chr15-73029165;