15-72727990-T-C

Variant names:

• chr15-72727990-T-C
• rs1060503692
• NM_033028.5:c.638T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033028.5(BBS4):​c.638T>C​(p.Leu213Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L213L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS4 NM_033028.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS4	NM_033028.5	c.638T>C	p.Leu213Ser	missense_variant	Exon 9 of 16	ENST00000268057.9	NP_149017.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS4	ENST00000268057.9	c.638T>C	p.Leu213Ser	missense_variant	Exon 9 of 16	1	NM_033028.5	ENSP00000268057.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	.;D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.6	.;L;.
PhyloP100		7.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.5	.;D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.90
MutPred		0.73		.;Loss of stability (P = 0.0254);.;
MVP		0.94
MPC		0.023
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.69
Mutation Taster		=35/65	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060503692; hg19: chr15-73020331;