chr2-169479554-A-G

Position:

• chr2-169479554-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The NM_152384.3(BBS5):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000205 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BBS5 NM_152384.3 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.89

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 13 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_152384.3 (BBS5) was described as [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-169479554-A-G is Pathogenic according to our data. Variant chr2-169479554-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1679817.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS5	NM_152384.3	c.1A>G	p.Met1?	start_lost	1/12	ENST00000295240.8	NP_689597.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS5	ENST00000295240.8	c.1A>G	p.Met1?	start_lost	1/12	1	NM_152384.3	ENSP00000295240	P1
BBS5	ENST00000392663.6	c.1A>G	p.Met1?	start_lost	1/11	1		ENSP00000376431
BBS5	ENST00000469980.1	n.75A>G		non_coding_transcript_exon_variant	1/2	4
BBS5	ENST00000443151.1	c.1A>G	p.Met1?	start_lost, NMD_transcript_variant	1/6	5		ENSP00000406182

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461828 Hom.: 0 Cov.: 34 AF XY: 0.00000413 AC XY: 3 AN XY: 727220

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bardet-Biedl syndrome 5 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory of Nephrology, Qingdao Municipal Hospital

Oct 05, 2021

NM_152384.3:c.1A>G,( p.Met1?) is an initiation codon variant, other different variants at the same amino acid position have been reported (Am J Ophthalmol. 2015;160(2):364-372.e1.;Hum Genet. 2010;127(5):583-593.& J Med Genet. 2010;47(4):262-267.). On the other allele of our patient, a large deletion c.(?_-60)_(386+1_387-1)del spanning 8.5 kb which correponding to exon 1-5 is obviously deleterious. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.
Eigen	Benign	0.059
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Benign	-0.54	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.81	N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.017	D;D;D
Sift4G	Benign	0.73	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.94
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.063);Gain of catalytic residue at M1 (P = 0.063);Gain of catalytic residue at M1 (P = 0.063);
MVP		0.84
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr2-170336064;