15-72686190-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000566400.6(BBS4):c.-507C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0662 in 1,549,504 control chromosomes in the GnomAD database, including 3,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.047 ( 239 hom., cov: 32)

Exomes 𝑓: 0.068 ( 3734 hom. )

Consequence

BBS4
ENST00000566400.6 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.77

Publications

19 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 links:

HIGD2B (HGNC:26984): (HIG1 hypoxia inducible domain family member 2B) Predicted to be involved in mitochondrial respirasome assembly. Predicted to be integral component of membrane. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

HIGD2B 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=-0.81).

BP6

Variant 15-72686190-C-A is Benign according to our data. Variant chr15-72686190-C-A is described in ClinVar as Benign. ClinVar VariationId is 262133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS4	NM_033028.5 link	c.-38C>A		upstream_gene_variant		ENST00000268057.9	NP_149017.2
HIGD2B	NM_001350932.3 link	c.-565G>T		upstream_gene_variant		ENST00000311755.6	NP_001337861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS4	ENST00000268057.9 link	c.-38C>A		upstream_gene_variant		1	NM_033028.5	ENSP00000268057.4
HIGD2B	ENST00000311755.6 link	c.-565G>T		upstream_gene_variant		1	NM_001350932.3	ENSP00000307951.3

Frequencies

GnomAD3 genomes

AF:

0.0471

AC:

7164

AN:

152216

Hom.:

239

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.0921

Gnomad AMR

AF:

0.0376

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0211

Gnomad FIN

AF:

0.0634

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0729

Gnomad OTH

AF:

0.0488

GnomAD2 exomes

AF:

0.0458

AC:

7214

AN:

157460

AF XY:

0.0453

show subpopulations

Gnomad AFR exome

AF:

0.00973

Gnomad AMR exome

AF:

0.0352

Gnomad ASJ exome

AF:

0.0235

Gnomad EAS exome

AF:

0.0000851

Gnomad FIN exome

AF:

0.0606

Gnomad NFE exome

AF:

0.0725

Gnomad OTH exome

AF:

0.0465

GnomAD4 exome

AF:

0.0683

AC:

95471

AN:

1397170

Hom.:

3734

Cov.:

AF XY:

0.0672

AC XY:

46327

AN XY:

689498

show subpopulations

African (AFR)

AF:

0.00979

AC:

311

AN:

31762

American (AMR)

AF:

0.0360

AC:

1295

AN:

36016

Ashkenazi Jewish (ASJ)

AF:

0.0215

AC:

543

AN:

25202

East Asian (EAS)

AF:

0.000111

AC:

AN:

36054

South Asian (SAS)

AF:

0.0217

AC:

1718

AN:

79276

European-Finnish (FIN)

AF:

0.0584

AC:

2767

AN:

47354

Middle Eastern (MID)

AF:

0.00773

AC:

AN:

4142

European-Non Finnish (NFE)

AF:

0.0794

AC:

85665

AN:

1079472

Other (OTH)

AF:

0.0542

AC:

3136

AN:

57892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

5055

10111

15166

20222

25277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3200

6400

9600

12800

16000

<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:

0.0470

AC:

7163

AN:

152334

Hom.:

239

Cov.:

AF XY:

0.0453

AC XY:

3378

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.0144

AC:

599

AN:

41584

American (AMR)

AF:

0.0375

AC:

573

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0211

AC:

102

AN:

4830

European-Finnish (FIN)

AF:

0.0634

AC:

674

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0729

AC:

4956

AN:

68020

Other (OTH)

AF:

0.0478

AC:

101

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

363

725

1088

1450

1813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<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:

0.0646

Hom.:

532

Bravo

AF:

0.0438

Asia WGS

AF:

0.00779

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Bardet-Biedl syndrome 4

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.030

(source)

DANN

Benign

0.86

PhyloP100

-2.8

PromoterAI

0.30

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over