4-121847465-T-C

Variant names:

• chr4-121847465-T-C
• rs863224815
• NM_176824.3:c.976A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_176824.3(BBS7):​c.976A>G​(p.Ser326Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS7 NM_176824.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64
• 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ciliopathy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 ciliopathy, Bardet-Biedl syndrome 7, Bardet-Biedl syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04780227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS7	NM_176824.3	c.976A>G	p.Ser326Gly	missense_variant	Exon 10 of 19	ENST00000264499.9	NP_789794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS7	ENST00000264499.9	c.976A>G	p.Ser326Gly	missense_variant	Exon 10 of 19	1	NM_176824.3	ENSP00000264499.4
BBS7	ENST00000506636.1	c.976A>G	p.Ser326Gly	missense_variant	Exon 10 of 18	1		ENSP00000423626.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bardet-Biedl syndrome Uncertain:1

Dec 15, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 216829). This missense change has been observed in individual(s) with Bardet-Biedl syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 326 of the BBS7 protein (p.Ser326Gly). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-0.20	N;N
PhyloP100		1.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.28
Sift	Benign	0.28	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0	B;.
Vest4		0.079
MutPred		0.14		Loss of glycosylation at K324 (P = 0.0457);Loss of glycosylation at K324 (P = 0.0457);
MVP		0.88
MPC		0.15
ClinPred		0.16	T
GERP RS		2.0
Varity_R		0.048
gMVP		0.18
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863224815; hg19: chr4-122768620;