chr15-72686244-T-G

Position:

• chr15-72686244-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033028.5(BBS4):​c.17T>G​(p.Val6Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000495 in 1,413,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V6A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: BBS4 NM_033028.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.102

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06361553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS4	NM_033028.5	c.17T>G	p.Val6Gly	missense_variant	1/16	ENST00000268057.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS4	ENST00000268057.9	c.17T>G	p.Val6Gly	missense_variant	1/16	1	NM_033028.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000495 AC: 7 AN: 1413276 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698472

Gnomad4 AFR exome AF: 0.0000310

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000270

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000368

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

BBS4-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2024

The BBS4 c.17T>G variant is predicted to result in the amino acid substitution p.Val6Gly. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	6.1
DANN	Benign	0.89
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.24	N;N
REVEL	Benign	0.20
Sift	Benign	0.31	T;T
Sift4G	Benign	0.32	T;D
Polyphen		0.0020	B;.
Vest4		0.23
MutPred		0.23		Loss of stability (P = 0.009);.;
MVP		0.33
MPC		0.012
ClinPred		0.23	T
GERP RS		-1.5
Varity_R		0.087
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-72978585;