dbSNP rs150754122: BBS4:c.712-17C>G (chr15-72731288-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_033028.5(BBS4):c.712-17C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,613,960 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 14 hom., cov: 29)

Exomes 𝑓: 0.015 ( 187 hom. )

Consequence

BBS4
NM_033028.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.50

Publications

0 publications found

Variant links:

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]

BBS4 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
BBS4-related ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 15-72731288-C-G is Benign according to our data. Variant chr15-72731288-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0103 (1562/152130) while in subpopulation NFE AF = 0.0168 (1143/67974). AF 95% confidence interval is 0.016. There are 14 homozygotes in GnomAd4. There are 678 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033028.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BBS4	NM_033028.5	MANE Select	c.712-17C>G	intron	N/A	NP_149017.2
BBS4	NM_001320665.2		c.643-17C>G	intron	N/A	NP_001307594.1	H3BSL2
BBS4	NM_001252678.2		c.196-17C>G	intron	N/A	NP_001239607.1	Q96RK4-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BBS4	ENST00000268057.9	TSL:1 MANE Select	c.712-17C>G	intron	N/A	ENSP00000268057.4	Q96RK4-1
BBS4	ENST00000395205.7	TSL:1	c.196-17C>G	intron	N/A	ENSP00000378631.3	Q96RK4-3
BBS4	ENST00000566400.6	TSL:1	c.196-17C>G	intron	N/A	ENSP00000456759.2	H3BSL3

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1561

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00273

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.00936

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00291

Gnomad FIN

AF:

0.00473

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0168

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00963

AC:

2422

AN:

251454

AF XY:

0.00937

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.0143

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00411

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.00831

GnomAD4 exome

AF:

0.0148

AC:

21610

AN:

1461830

Hom.:

187

Cov.:

AF XY:

0.0145

AC XY:

10512

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00224

AC:

AN:

33478

American (AMR)

AF:

0.00657

AC:

294

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0139

AC:

364

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00357

AC:

308

AN:

86246

European-Finnish (FIN)

AF:

0.00431

AC:

230

AN:

53412

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0175

AC:

19457

AN:

1111976

Other (OTH)

AF:

0.0141

AC:

852

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1201

2401

3602

4802

6003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

720

1440

2160

2880

3600

<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:

0.0103

AC:

1562

AN:

152130

Hom.:

Cov.:

AF XY:

0.00912

AC XY:

678

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00272

AC:

113

AN:

41516

American (AMR)

AF:

0.00935

AC:

143

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00291

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00473

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0168

AC:

1143

AN:

67974

Other (OTH)

AF:

0.0147

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

148

221

295

369

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0138

Hom.:

Bravo

AF:

0.0105

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bardet-Biedl syndrome (1)

Bardet-Biedl syndrome 4 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.0070

(source)

DANN

Benign

0.48

PhyloP100

-1.5

PromoterAI

0.0012

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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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