dbSNP rs137853921: BBS5:p.Asn184Ser (chr2-169493769-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_152384.3(BBS5):c.551A>G(p.Asn184Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00506 in 1,612,686 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0038 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 21 hom. )

Consequence

BBS5
NM_152384.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:9O:1

Conservation

PhyloP100: 9.32

Publications

25 publications found

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 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 5
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P
BBS5-related ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS5 links:

ENSG00000251569 (HGNC:):

ENSG00000251569 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_152384.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.85025 (below the threshold of 3.09). Trascript score misZ: 1.0056 (below the threshold of 3.09). GenCC associations: The gene is linked to Bardet-Biedl syndrome 5, BBS5-related ciliopathy, Bardet-Biedl syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.029099584).

BP6

Variant 2-169493769-A-G is Benign according to our data. Variant chr2-169493769-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 100605.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00376 (572/152322) while in subpopulation NFE AF = 0.00635 (432/68030). AF 95% confidence interval is 0.00586. There are 2 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS5	NM_152384.3	MANE Select	c.551A>G	p.Asn184Ser	missense	Exon 7 of 12	NP_689597.1	A0A0S2Z626

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BBS5	ENST00000295240.8	TSL:1 MANE Select	c.551A>G	p.Asn184Ser	missense	Exon 7 of 12	ENSP00000295240.3	Q8N3I7-1
ENSG00000251569	ENST00000513963.1	TSL:2	c.551A>G	p.Asn184Ser	missense	Exon 7 of 16	ENSP00000424363.1	E9PBE3
BBS5	ENST00000392663.6	TSL:1	c.551A>G	p.Asn184Ser	missense	Exon 7 of 11	ENSP00000376431.2	Q8N3I7-2

Frequencies

GnomAD3 genomes

AF:

0.00376

AC:

572

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00489

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00635

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00419

AC:

1053

AN:

251288

AF XY:

0.00426

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.00456

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00480

Gnomad NFE exome

AF:

0.00698

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00520

AC:

7593

AN:

1460364

Hom.:

Cov.:

AF XY:

0.00519

AC XY:

3772

AN XY:

726556

show subpopulations

African (AFR)

AF:

0.000688

AC:

AN:

33436

American (AMR)

AF:

0.00148

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00414

AC:

108

AN:

26118

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39606

South Asian (SAS)

AF:

0.000754

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00476

AC:

254

AN:

53416

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00613

AC:

6813

AN:

1110760

Other (OTH)

AF:

0.00401

AC:

242

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

347

693

1040

1386

1733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

238

476

714

952

1190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00376

AC:

572

AN:

152322

Hom.:

Cov.:

AF XY:

0.00342

AC XY:

255

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41574

American (AMR)

AF:

0.00137

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00125

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00489

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00635

AC:

432

AN:

68030

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

120

150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00560

Hom.:

Bravo

AF:

0.00346

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00438

AC:

532

Asia WGS

AF:

0.00116

AC:

AN:

3472

EpiCase

AF:

0.00616

EpiControl

AF:

0.00747

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

Bardet-Biedl syndrome (1)

Cone dystrophy (1)

Intellectual disability (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.029

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.0

PhyloP100

9.3

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.93

MVP

0.94

MPC

0.96

ClinPred

0.038

GERP RS

6.0

Varity_R

0.72

gMVP

0.68

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over