2-169479555-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_152384.3(BBS5):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000479 in 1,461,838 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (1 hom.)
• Consequence: BBS5 NM_152384.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.05

Genes affected

BBS5 (HGNC:970): (Bardet-Biedl syndrome 5) This gene encodes a protein that has been directly linked to Bardet-Biedl syndrome. The primary features of this syndrome include retinal dystrophy, obesity, polydactyly, renal abnormalities and learning disabilities. Experimentation in non-human eukaryotes suggests that this gene is expressed in ciliated cells and that it is required for the formation of cilia. Alternate transcriptional splice variants have been observed but have not been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_152384.3 (BBS5) was described as [Pathogenic] in ClinVar as 1679817
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-169479555-T-A is Pathogenic according to our data. Variant chr2-169479555-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 812118.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-169479555-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS5	NM_152384.3	c.2T>A	p.Met1?	start_lost	1/12	ENST00000295240.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS5	ENST00000295240.8	c.2T>A	p.Met1?	start_lost	1/12	1	NM_152384.3	P1
BBS5	ENST00000392663.6	c.2T>A	p.Met1?	start_lost	1/11	1
BBS5	ENST00000469980.1	n.76T>A		non_coding_transcript_exon_variant	1/2	4
BBS5	ENST00000443151.1	c.2T>A	p.Met1?	start_lost, NMD_transcript_variant	1/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249784 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135168

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461838 Hom.: 1 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bardet-Biedl syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Feb 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Benign	-0.43	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.12	N;N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.0080	B;B;.
Vest4		0.94
MutPred		0.95		Gain of helix (P = 0.027);Gain of helix (P = 0.027);Gain of helix (P = 0.027);
MVP		0.95
ClinPred		0.91	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs767822498; hg19: chr2-170336065;