rs7665271

chr4-122743178-G-Achr4-122743178-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_152618.3(BBS12):c.1286G>A(p.Ser429Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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. S429T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BBS12 NM_152618.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.142

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_152618.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07279584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS12	NM_152618.3	c.1286G>A	p.Ser429Asn	missense_variant	2/2	ENST00000314218.8
BBS12	NM_001178007.2	c.1286G>A	p.Ser429Asn	missense_variant	3/3
BBS12	XM_011531680.3	c.1286G>A	p.Ser429Asn	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS12	ENST00000314218.8	c.1286G>A	p.Ser429Asn	missense_variant	2/2	1	NM_152618.3	P1
BBS12	ENST00000542236.5	c.1286G>A	p.Ser429Asn	missense_variant	3/3	2		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 71 AF XY: 0.00 AC XY: 0 AN XY: 727244

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.87
Dann	Benign	0.65
DEOGEN2	Benign	0.10	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.52	T;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.092
Sift	Benign	0.36	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0070	B;B
Vest4		0.038
MutPred		0.30		Loss of catalytic residue at K430 (P = 0.0993);Loss of catalytic residue at K430 (P = 0.0993);
MVP		0.61
MPC		0.088
ClinPred		0.21	T
GERP RS		-0.60
Varity_R		0.040
gMVP		0.30

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: rs7665271; hg19: chr4-123664333;