4-122742947-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_152618.3(BBS12):c.1055A>G(p.Gln352Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q352P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BBS12 NM_152618.3 missense
• Clinical Significance: Not reported in ClinVar
• 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
• PM5: Other missense variant is known to change same aminoacid residue: 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=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09997806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS12	NM_152618.3	c.1055A>G	p.Gln352Arg	missense_variant	2/2	ENST00000314218.8
BBS12	NM_001178007.2	c.1055A>G	p.Gln352Arg	missense_variant	3/3
BBS12	XM_011531680.3	c.1055A>G	p.Gln352Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS12	ENST00000314218.8	c.1055A>G	p.Gln352Arg	missense_variant	2/2	1	NM_152618.3	P1
BBS12	ENST00000542236.5	c.1055A>G	p.Gln352Arg	missense_variant	3/3	2		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727214

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	14
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.47	T;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	0.58	D;D
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.12
Sift	Benign	0.32	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0030	B;B
Vest4		0.094
MutPred		0.45		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.92
MPC		0.11
ClinPred		0.11	T
GERP RS		0.76
Varity_R		0.079
gMVP		0.34

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;