NM_152618.3:c.27_30delCAAA

Variant names:

• chr4-122741915-TAAAC-T
• NM_152618.3:c.27_30delCAAA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_152618.3(BBS12):​c.27_30delCAAA​(p.Asn9LysfsTer21) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BBS12 NM_152618.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.26

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-122741915-TAAAC-T is Pathogenic according to our data. Variant chr4-122741915-TAAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 1384347.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBS12	NM_152618.3	c.27_30delCAAA	p.Asn9LysfsTer21	frameshift_variant	Exon 2 of 2	ENST00000314218.8	NP_689831.2
BBS12	NM_001178007.2	c.27_30delCAAA	p.Asn9LysfsTer21	frameshift_variant	Exon 3 of 3		NP_001171478.1
BBS12	XM_011531680.3	c.27_30delCAAA	p.Asn9LysfsTer21	frameshift_variant	Exon 2 of 2		XP_011529982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBS12	ENST00000314218.8	c.27_30delCAAA	p.Asn9LysfsTer21	frameshift_variant	Exon 2 of 2	1	NM_152618.3	ENSP00000319062.3
BBS12	ENST00000542236.5	c.27_30delCAAA	p.Asn9LysfsTer21	frameshift_variant	Exon 3 of 3	2		ENSP00000438273.1
BBS12	ENST00000433287.1	c.27_30delCAAA	p.Asn9LysfsTer21	frameshift_variant	Exon 3 of 3	2		ENSP00000398912.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bardet-Biedl syndrome Pathogenic:1

Mar 10, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn9Lysfs*21) in the BBS12 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 702 amino acid(s) of the BBS12 protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BBS12-related conditions. This variant disrupts the C-terminus of the BBS12 protein. Other variant(s) that disrupt this region (p.Asp687Valfs*3) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-123663070;