chr4-122741893-A-C

Position:

chr4-122741893-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_152618.3(BBS12):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,613,826 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000064 ( 1 hom. )

Consequence

BBS12
NM_152618.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:5

Conservation

PhyloP100: -0.323

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_152618.3 (BBS12) was described as [Conflicting_classifications_of_pathogenicity] in ClinVar as 556158

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
BBS12	NM_152618.3 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	2/2	ENST00000314218.8
BBS12	NM_001178007.2 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	3/3
BBS12	XM_011531680.3 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
BBS12	ENST00000314218.8 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	2/2	1	NM_152618.3	P1
BBS12	ENST00000542236.5 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	3/3	2		P1
BBS12	ENST00000433287.1 linkuse as main transcript	c.1A>C	p.Met1?	start_lost	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251192

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461592

Hom.:

Cov.:

AF XY:

0.0000866

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000545

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000718

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bardet-Biedl syndrome 12

Pathogenic:1Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 22, 2020	- -
Likely pathogenic, flagged submission	clinical testing	Counsyl	May 08, 2017	- -

BBS12-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2023

The BBS12 c.1A>C variant is predicted to disrupt the translation initiation site (Start loss). However, an in-frame methionine (potential alternative start codon) is present at the third codon. This variant was documented in a family with recessive form of retinitis pigmentosa (Table S5 - Watson et al. 2014. PubMed ID: 25133751). This variant is reported in 0.049% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-123663048-A-C). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2021

The c.1A>C (p.M1?) alteration is located in coding exon 1 of the BBS12 gene and consists of a A to C substitution at nucleotide position 1. This changes the amino acid from a methionine to a (?) at the initiation codon. Sequence variations that modify the initiation codon (ATG) are expected to cause a shift in the mRNA reading frame and are typically deleterious in nature (Richards, 2015). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BBS12 p.M1? variant was not identified in the literature but was identified in dbSNP (ID: rs750366365) and ClinVar (classified as uncertain significance by Invitae and as likely pathogenic by Counsyl). The variant was identified in control databases in 31 of 282602 chromosomes at a frequency of 0.0001097 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.M1? variant results in the loss of the initiation codon however the next in-frame initiation codon occurs two codons downstream, therefore it is unclear how this may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Bardet-Biedl syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

This sequence change affects the initiator methionine of the BBS12 mRNA. The next in-frame methionine is located at codon 3. This variant is present in population databases (rs750366365, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with BBS12-related conditions. ClinVar contains an entry for this variant (Variation ID: 551815). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.17

DANN

Benign

0.70

DEOGEN2

Benign

0.036

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Benign

0.0095

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Benign

-0.92

MutationTaster

Benign

1.0

N;N

PROVEAN

Benign

-0.70

N;N;N

REVEL

Benign

0.16

Sift

Pathogenic

0.0

D;D;D

Sift4G

Benign

0.14

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.092

MutPred

0.96

Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);

MVP

0.87

ClinPred

0.025

GERP RS

1.6

Varity_R

0.76

gMVP

0.10

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over