4-122743273-A-T

Position:

• chr4-122743273-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152618.3(BBS12):​c.1381A>T​(p.Asn461Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. N461H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BBS12 NM_152618.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.57

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS12	NM_152618.3	c.1381A>T	p.Asn461Tyr	missense_variant	2/2	ENST00000314218.8	NP_689831.2
BBS12	NM_001178007.2	c.1381A>T	p.Asn461Tyr	missense_variant	3/3		NP_001171478.1
BBS12	XM_011531680.3	c.1381A>T	p.Asn461Tyr	missense_variant	2/2		XP_011529982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS12	ENST00000314218.8	c.1381A>T	p.Asn461Tyr	missense_variant	2/2	1	NM_152618.3	ENSP00000319062	P1
BBS12	ENST00000542236.5	c.1381A>T	p.Asn461Tyr	missense_variant	3/3	2		ENSP00000438273	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;D
Eigen	Benign	0.14
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.66	T;.
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.63	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.94	P;P
Vest4		0.47
MutPred		0.43		Loss of catalytic residue at N461 (P = 0.0744);Loss of catalytic residue at N461 (P = 0.0744);
MVP		0.90
MPC		0.47
ClinPred		0.97	D
GERP RS		0.49
Varity_R		0.27
gMVP		0.45

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: rs10027479; hg19: chr4-123664428;