4-122743273-A-C

Variant names:

Variant summary

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

The NM_152618.3(BBS12):c.1381A>C(p.Asn461His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00423 in 1,614,222 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N461S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.023 ( 136 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 119 hom. )

Consequence

BBS12
NM_152618.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 2.57

Publications

11 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, G2P, Ambry Genetics, Myriad Women’s Health
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023567379).

BP6

Variant 4-122743273-A-C is Benign according to our data. Variant chr4-122743273-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 100564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0784 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.1381A>C	p.Asn461His	missense	Exon 2 of 2	NP_689831.2
	BBS12	NM_001178007.2		c.1381A>C	p.Asn461His	missense	Exon 3 of 3	NP_001171478.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS12	ENST00000314218.8	TSL:1 MANE Select	c.1381A>C	p.Asn461His	missense	Exon 2 of 2	ENSP00000319062.3
	BBS12	ENST00000542236.5	TSL:2	c.1381A>C	p.Asn461His	missense	Exon 3 of 3	ENSP00000438273.1

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3528

AN:

152218

Hom.:

135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0807

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00778

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.00591

AC:

1487

AN:

251466

AF XY:

0.00435

show subpopulations

Gnomad AFR exome

AF:

0.0826

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00225

AC:

3288

AN:

1461886

Hom.:

119

Cov.:

AF XY:

0.00198

AC XY:

1438

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0809

AC:

2709

AN:

33480

American (AMR)

AF:

0.00376

AC:

168

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000106

AC:

118

AN:

1112006

Other (OTH)

AF:

0.00447

AC:

270

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

214

428

642

856

1070

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0232

AC:

3537

AN:

152336

Hom.:

136

Cov.:

AF XY:

0.0228

AC XY:

1697

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0807

AC:

3352

AN:

41562

American (AMR)

AF:

0.00777

AC:

119

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68028

Other (OTH)

AF:

0.0199

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

176

353

529

706

882

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00820

Hom.:

Bravo

AF:

0.0263

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0837

AC:

369

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00773

AC:

938

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Bardet-Biedl syndrome 1 (2)

Bardet-Biedl syndrome 12 (2)

Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.6

PhyloP100

2.6

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.15

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.017

Polyphen

0.25

Vest4

0.30

MVP

0.70

MPC

0.44

ClinPred

0.045

GERP RS

0.49

Varity_R

0.14

gMVP

0.38

Mutation Taster

=98/2

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