Genetic Variant BBS4:c.1249-35G>C (chr15-72736727-G-C) – 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.1249-35G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 1,609,610 control chromosomes in the GnomAD database, including 1,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 57 hom., cov: 32)

Exomes 𝑓: 0.034 ( 983 hom. )

Consequence

BBS4
NM_033028.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.215

Publications

3 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:

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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=-0.83).

BP6

Variant 15-72736727-G-C is Benign according to our data. Variant chr15-72736727-G-C is described in ClinVar as Benign. ClinVar VariationId is 262137.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 = 0.0258 (3922/152282) while in subpopulation NFE AF = 0.0361 (2456/68024). AF 95% confidence interval is 0.0349. There are 57 homozygotes in GnomAd4. There are 1821 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 57 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.1249-35G>C	intron	N/A	NP_149017.2
BBS4	NM_001320665.2		c.1180-35G>C	intron	N/A	NP_001307594.1	H3BSL2
BBS4	NM_001252678.2		c.733-35G>C	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.1249-35G>C	intron	N/A	ENSP00000268057.4	Q96RK4-1
BBS4	ENST00000395205.7	TSL:1	c.733-35G>C	intron	N/A	ENSP00000378631.3	Q96RK4-3
BBS4	ENST00000566400.6	TSL:1	c.733-35G>C	intron	N/A	ENSP00000456759.2	H3BSL3

Frequencies

GnomAD3 genomes

AF:

0.0257

AC:

3912

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00697

Gnomad AMI

AF:

0.0822

Gnomad AMR

AF:

0.0332

Gnomad ASJ

AF:

0.0380

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.0277

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0361

Gnomad OTH

AF:

0.0278

GnomAD2 exomes

AF:

0.0306

AC:

7643

AN:

249830

AF XY:

0.0309

show subpopulations

Gnomad AFR exome

AF:

0.00629

Gnomad AMR exome

AF:

0.0359

Gnomad ASJ exome

AF:

0.0411

Gnomad EAS exome

AF:

0.00181

Gnomad FIN exome

AF:

0.0299

Gnomad NFE exome

AF:

0.0396

Gnomad OTH exome

AF:

0.0382

GnomAD4 exome

AF:

0.0341

AC:

49766

AN:

1457328

Hom.:

983

Cov.:

AF XY:

0.0340

AC XY:

24624

AN XY:

725302

show subpopulations

African (AFR)

AF:

0.00665

AC:

222

AN:

33370

American (AMR)

AF:

0.0359

AC:

1604

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.0399

AC:

1042

AN:

26106

East Asian (EAS)

AF:

0.00111

AC:

AN:

39662

South Asian (SAS)

AF:

0.0164

AC:

1409

AN:

86112

European-Finnish (FIN)

AF:

0.0302

AC:

1610

AN:

53394

Middle Eastern (MID)

AF:

0.0295

AC:

166

AN:

5624

European-Non Finnish (NFE)

AF:

0.0377

AC:

41818

AN:

1108174

Other (OTH)

AF:

0.0307

AC:

1851

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

2628

5256

7883

10511

13139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1552

3104

4656

6208

7760

<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:

0.0258

AC:

3922

AN:

152282

Hom.:

Cov.:

AF XY:

0.0245

AC XY:

1821

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00705

AC:

293

AN:

41568

American (AMR)

AF:

0.0332

AC:

507

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0380

AC:

132

AN:

3470

East Asian (EAS)

AF:

0.00231

AC:

AN:

5190

South Asian (SAS)

AF:

0.0184

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0277

AC:

294

AN:

10602

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0361

AC:

2456

AN:

68024

Other (OTH)

AF:

0.0285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

189

378

566

755

944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0175

Hom.:

Bravo

AF:

0.0261

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.7

(source)

DANN

Benign

0.35

PhyloP100

-0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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