2-169479554-A-T

Position:

chr2-169479554-A-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_152384.3(BBS5):c.1A>T(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000186 in 1,614,128 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BBS5
NM_152384.3 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 5.89

Variant links:

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]

BBS5 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 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-T is Pathogenic according to our data. Variant chr2-169479554-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3014382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS5	NM_152384.3 linkuse as main transcript	c.1A>T	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 linkuse as main transcript	c.1A>T	p.Met1?	start_lost	1/12	1	NM_152384.3	ENSP00000295240	P1	Q8N3I7-1
BBS5	ENST00000392663.6 linkuse as main transcript	c.1A>T	p.Met1?	start_lost	1/11	1		ENSP00000376431		Q8N3I7-2
BBS5	ENST00000469980.1 linkuse as main transcript	n.75A>T		non_coding_transcript_exon_variant	1/2	4
BBS5	ENST00000443151.1 linkuse as main transcript	c.1A>T	p.Met1?	start_lost, NMD_transcript_variant	1/6	5		ENSP00000406182

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249786

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135166

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2023

For these reasons, this variant has been classified as Pathogenic. Disruption of the initiator codon has been observed in individual(s) with Bardet-Biedl syndrome (PMID: 19797195, 25982971). This variant is present in population databases (rs536117380, gnomAD 0.007%). This sequence change affects the initiator methionine of the BBS5 mRNA. The next in-frame methionine is located at codon 22. -

Bardet-Biedl syndrome 5

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.14

T;.;.

Eigen

Benign

0.0085

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Benign

-0.68

MutationTaster

Benign

1.0

D;D;D

PROVEAN

Benign

-0.87

N;N;N

REVEL

Uncertain

0.36

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.58

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.93

MutPred

0.96

Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);

MVP

0.80

ClinPred

0.92

GERP RS

6.0

Varity_R

0.32

gMVP

0.31

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over