chr4-122743178-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_152618.3(BBS12):c.1286G>C(p.Ser429Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,614,148 control chromosomes in the GnomAD database, including 488 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S429S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.032 ( 280 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 208 hom. )

Consequence

BBS12
NM_152618.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.142

Publications

9 publications found

Variant links:

Genes affected

BBS12 (HGNC:26648): (Bardet-Biedl syndrome 12) The protein encoded by this gene is part of a complex that is involved in membrane trafficking. The encoded protein is a molecular chaperone that aids in protein folding upon ATP hydrolysis. This protein also plays a role in adipocyte differentiation. Defects in this gene are a cause of Bardet-Biedl syndrome type 12. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

BBS12 Gene-Disease associations (from GenCC):

Bardet-Biedl syndrome 12
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Myriad Women’s Health, G2P, Ambry Genetics
BBS12-related ciliopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
Bardet-Biedl syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

BBS12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_152618.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0018096864).

BP6

Variant 4-122743178-G-C is Benign according to our data. Variant chr4-122743178-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152618.3. 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
	BBS12	NM_152618.3	MANE Select	c.1286G>C	p.Ser429Thr	missense	Exon 2 of 2	NP_689831.2
	BBS12	NM_001178007.2		c.1286G>C	p.Ser429Thr	missense	Exon 3 of 3	NP_001171478.1	Q6ZW61

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS12	ENST00000314218.8	TSL:1 MANE Select	c.1286G>C	p.Ser429Thr	missense	Exon 2 of 2	ENSP00000319062.3	Q6ZW61
	BBS12	ENST00000542236.5	TSL:2	c.1286G>C	p.Ser429Thr	missense	Exon 3 of 3	ENSP00000438273.1	Q6ZW61

Frequencies

GnomAD3 genomes

AF:

0.0317

AC:

4828

AN:

152142

Hom.:

279

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0181

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0239

GnomAD2 exomes

AF:

0.00899

AC:

2261

AN:

251468

AF XY:

0.00629

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.00833

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000668

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00368

AC:

5377

AN:

1461888

Hom.:

208

Cov.:

AF XY:

0.00312

AC XY:

2268

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.112

AC:

3735

AN:

33478

American (AMR)

AF:

0.00783

AC:

350

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00907

AC:

237

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000290

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000456

AC:

507

AN:

1112012

Other (OTH)

AF:

0.00806

AC:

487

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

362

724

1086

1448

1810

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<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:

0.0318

AC:

4840

AN:

152260

Hom.:

280

Cov.:

AF XY:

0.0309

AC XY:

2298

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.107

AC:

4425

AN:

41532

American (AMR)

AF:

0.0181

AC:

277

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68022

Other (OTH)

AF:

0.0237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

226

452

678

904

1130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.00353

Hom.:

Bravo

AF:

0.0367

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.102

AC:

451

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.0105

AC:

1277

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.00130

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 (3)

not specified (3)

Bardet-Biedl syndrome 12 (2)

not provided (2)

Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.24

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.14

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

REVEL

Benign

0.15

Sift

Benign

0.48

Sift4G

Benign

0.47

Polyphen

0.028

Vest4

0.043

MPC

0.095

ClinPred

0.0012

GERP RS

-0.60

Varity_R

0.053

gMVP

0.34

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over