4-122741893-A-G

Position:

• chr4-122741893-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_152618.3(BBS12):​c.1A>G​(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 0.00000479 in 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: BBS12 NM_152618.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.323

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS12	NM_152618.3	c.1A>G	p.Met1?	start_lost	2/2	ENST00000314218.8	NP_689831.2
BBS12	NM_001178007.2	c.1A>G	p.Met1?	start_lost	3/3		NP_001171478.1
BBS12	XM_011531680.3	c.1A>G	p.Met1?	start_lost	2/2		XP_011529982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS12	ENST00000314218.8	c.1A>G	p.Met1?	start_lost	2/2	1	NM_152618.3	ENSP00000319062	P1
BBS12	ENST00000542236.5	c.1A>G	p.Met1?	start_lost	3/3	2		ENSP00000438273	P1
BBS12	ENST00000433287.1	c.1A>G	p.Met1?	start_lost	3/3	2		ENSP00000398912

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251192 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135804

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461592 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727124

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	1.5
DANN	Benign	0.89
DEOGEN2	Benign	0.045	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.083	N
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	-0.73	N;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.0050	B;B;.
Vest4		0.088
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0085);Gain of catalytic residue at M1 (P = 0.0085);Gain of catalytic residue at M1 (P = 0.0085);
MVP		0.88
ClinPred		0.053	T
GERP RS		1.6
Varity_R		0.71
gMVP		0.13

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: rs750366365; hg19: chr4-123663048;