4-121847490-CAG-GAC

Variant names:

• chr4-121847490-CAG-GAC
• NM_176824.3:c.949_951delCTGinsGTC
• BBS7 p.Leu317Val

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1 PP2 PP3

The NM_176824.3(BBS7):​c.949_951delCTGinsGTC​(p.Leu317Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L317Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS7 NM_176824.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

BBS7 (HGNC:18758): (Bardet-Biedl syndrome 7) This gene encodes one of eight proteins that form the BBSome complex containing BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10. The BBSome complex is believed to recruit Rab8(GTP) to the primary cilium and promote ciliogenesis. The BBSome complex assembly is mediated by a complex composed of three chaperonin-like BBS proteins (BBS6, BBS10, and BBS12) and CCT/TRiC family chaperonins. Mutations in this gene are implicated in Bardet-Biedl syndrome, a genetic disorder whose symptoms include obesity, retinal degeneration, polydactyly and nephropathy; however, mutations in this gene and the BBS8 gene are thought to play a minor role and mutations in chaperonin-like BBS genes are found to be a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population. Two transcript variants encoding distinct isoforms have been identified for this gene.[provided by RefSeq, Oct 2014]

BBS7 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• BBS7-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 6 ACMG points.

• PS1: Transcript NM_176824.3 (BBS7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.2326 (below the threshold of 3.09). Trascript score misZ: 1.7868 (below the threshold of 3.09). GenCC associations: The gene is linked to Bardet-Biedl syndrome, Bardet-Biedl syndrome 7, BBS7-related ciliopathy.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176824.3. 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
	BBS7	NM_176824.3	MANE Select	c.949_951delCTGinsGTC	p.Leu317Val	missense	N/A	NP_789794.1	Q8IWZ6-1
	BBS7	NM_018190.4		c.949_951delCTGinsGTC	p.Leu317Val	missense	N/A	NP_060660.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS7	ENST00000264499.9	TSL:1 MANE Select	c.949_951delCTGinsGTC	p.Leu317Val	missense	N/A	ENSP00000264499.4	Q8IWZ6-1
	BBS7	ENST00000506636.1	TSL:1	c.949_951delCTGinsGTC	p.Leu317Val	missense	N/A	ENSP00000423626.1	Q8IWZ6-2
	BBS7	ENST00000888033.1		c.997_999delCTGinsGTC	p.Leu333Val	missense	N/A	ENSP00000558092.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

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

hg19: chr4-122768645;