4-122742947-A-C

Position:

• chr4-122742947-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_152618.3(BBS12):​c.1055A>C​(p.Gln352Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: BBS12 NM_152618.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 2.28

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-122742947-A-C is Pathogenic according to our data. Variant chr4-122742947-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 560429.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}. Variant chr4-122742947-A-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.377338). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS12	NM_152618.3	c.1055A>C	p.Gln352Pro	missense_variant	2/2	ENST00000314218.8	NP_689831.2
BBS12	NM_001178007.2	c.1055A>C	p.Gln352Pro	missense_variant	3/3		NP_001171478.1
BBS12	XM_011531680.3	c.1055A>C	p.Gln352Pro	missense_variant	2/2		XP_011529982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS12	ENST00000314218.8	c.1055A>C	p.Gln352Pro	missense_variant	2/2	1	NM_152618.3	ENSP00000319062.3
BBS12	ENST00000542236.5	c.1055A>C	p.Gln352Pro	missense_variant	3/3	2		ENSP00000438273.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 251302 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 45 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.0000536 AC XY: 39 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bardet-Biedl syndrome 12 Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 08, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -

Bardet-Biedl syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2022	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 352 of the BBS12 protein (p.Gln352Pro). This variant is present in population databases (rs767068756, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Bardet-Biedl syndrome (PMID: 30614526). ClinVar contains an entry for this variant (Variation ID: 560429). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. -
Pathogenic, no assertion criteria provided	provider interpretation	Laboratory of Medical Genetics (UMR_S 1112), INSERM/Strasbourg University	Sep 15, 2018	- -

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

May 27, 2024

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 12, 2021

Variant summary: BBS12 c.1055A>C (p.Gln352Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251302 control chromosomes, predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. This frequency is somewhat lower than the maximum expected for a pathogenic variant in BBS12 causing Bardet-Biedl Syndrome (0.00076), allowing no conclusion about variant significance. The variant, c.1055A>C, has been reported in the literature in at least two apparently homozygous individuals with clinical features of Bardet-Biedl syndrome (Haer-Wigman_2017, Mary_2019). These data indicate that the variant maybe associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic (n=1) or VUS (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;D
Eigen	Benign	0.14
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.61	T;.
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.98	D;D
Vest4		0.39
MutPred		0.51		Gain of catalytic residue at Q352 (P = 0.0047);Gain of catalytic residue at Q352 (P = 0.0047);
MVP		0.89
MPC		0.49
ClinPred		0.39	T
GERP RS		0.76
Varity_R		0.40
gMVP		0.70

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: rs767068756; hg19: chr4-123664102;