chr4-122743929-A-C

Variant names:

• chr4-122743929-A-C
• rs1553941612
• NM_152618.3:c.2037A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152618.3(BBS12):​c.2037A>C​(p.Leu679Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. L679L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BBS12 NM_152618.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.555
• Publications: 0 publications found

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]

BBS12 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 12

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Ambry Genetics, Myriad Women’s Health
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152618.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS12	NM_152618.3	MANE Select	c.2037A>C	p.Leu679Phe	missense	Exon 2 of 2	NP_689831.2
	BBS12	NM_001178007.2		c.2037A>C	p.Leu679Phe	missense	Exon 3 of 3	NP_001171478.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS12	ENST00000314218.8	TSL:1 MANE Select	c.2037A>C	p.Leu679Phe	missense	Exon 2 of 2	ENSP00000319062.3
	BBS12	ENST00000542236.5	TSL:2	c.2037A>C	p.Leu679Phe	missense	Exon 3 of 3	ENSP00000438273.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.56
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.60		Gain of sheet (P = 0.0827)
MVP		0.91
MPC		0.47
ClinPred		0.99	D
GERP RS		-4.5
Varity_R		0.21
gMVP		0.59
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs1553941612; hg19: chr4-123665084;