rs77731085

chr4-122742247-G-Achr4-122742247-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152618.3(BBS12):c.355G>A(p.Gly119Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000938 in 1,613,782 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts 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. G119D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (4 hom.)
• Consequence: BBS12 NM_152618.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.11

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009709686).
• BP6: Variant 4-122742247-G-A is Benign according to our data. Variant chr4-122742247-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 215543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-122742247-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00411 (626/152244) while in subpopulation AFR AF= 0.0135 (561/41522). AF 95% confidence interval is 0.0126. There are 3 homozygotes in gnomad4. There are 313 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS12	NM_152618.3	c.355G>A	p.Gly119Ser	missense_variant	2/2	ENST00000314218.8
BBS12	NM_001178007.2	c.355G>A	p.Gly119Ser	missense_variant	3/3
BBS12	XM_011531680.3	c.355G>A	p.Gly119Ser	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS12	ENST00000314218.8	c.355G>A	p.Gly119Ser	missense_variant	2/2	1	NM_152618.3	P1
BBS12	ENST00000542236.5	c.355G>A	p.Gly119Ser	missense_variant	3/3	2		P1
BBS12	ENST00000433287.1	c.355G>A	p.Gly119Ser	missense_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 625 AN: 152126 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00160 AC: 398 AN: 249482 Hom.: 0 AF XY: 0.00115 AC XY: 155 AN XY: 135044

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00589

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000321

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000608 AC: 888 AN: 1461538 Hom.: 4 Cov.: 31 AF XY: 0.000494 AC XY: 359 AN XY: 727056

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00505

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00411 AC: 626 AN: 152244 Hom.: 3 Cov.: 33 AF XY: 0.00420 AC XY: 313 AN XY: 74446

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000974 Hom.: 2

Bravo AF: 0.00485

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00175 AC: 213

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -

Bardet-Biedl syndrome 12 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Bardet-Biedl syndrome Benign:2

Likely benign, criteria provided, single submitter	research	Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar	Nov 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

BBS12: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T;.;T
MetaRNN	Benign	0.0097	T;T;T
MetaSVM	Uncertain	0.028	D
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.072	T;T;D
Sift4G	Benign	0.12	T;T;D
Polyphen		1.0	D;D;.
Vest4		0.78
MVP		0.88
MPC		0.45
ClinPred		0.019	T
GERP RS		5.2
Varity_R		0.39
gMVP		0.59

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

Other links and lift over

dbSNP: rs77731085; hg19: chr4-123663402;