4-122732771-G-A

Variant names:

• chr4-122732771-G-A
• rs309358
• NM_152618.3:c.-124G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152618.3(BBS12):​c.-124G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.205 in 152,466 control chromosomes in the GnomAD database, including 3,498 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3494 hom., cov: 33)
  • Exomes 𝑓: 0.23 (4 hom.)
• Consequence: BBS12 NM_152618.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.452
• Publications: 6 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: Ambry Genetics, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• BBS12-related ciliopathy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000293471 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-122732771-G-A is Benign according to our data. Variant chr4-122732771-G-A is described in ClinVar as Benign. ClinVar VariationId is 347494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

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.-124G>A		5_prime_UTR	Exon 1 of 2	NP_689831.2
	BBS12	NM_001178007.2		c.-312G>A		5_prime_UTR	Exon 1 of 3	NP_001171478.1	Q6ZW61

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS12	ENST00000314218.8	TSL:1 MANE Select	c.-124G>A		5_prime_UTR	Exon 1 of 2	ENSP00000319062.3	Q6ZW61
	BBS12	ENST00000542236.5	TSL:2	c.-312G>A		5_prime_UTR	Exon 1 of 3	ENSP00000438273.1	Q6ZW61
	BBS12	ENST00000433287.1	TSL:2	c.-312G>A		upstream_gene	N/A	ENSP00000398912.1	C9J8H7

Frequencies

GnomAD3 genomes AF: 0.205 AC: 31138 AN: 152134 Hom.: 3493 Cov.: 33

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.187

GnomAD4 exome AF: 0.229 AC: 49 AN: 214 Hom.: 4 Cov.: 0 AF XY: 0.263 AC XY: 42 AN XY: 160

African (AFR) AF: 0.167 AC: 1 AN: 6

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.200 AC: 2 AN: 10

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.239 AC: 42 AN: 176

Other (OTH) AF: 0.143 AC: 2 AN: 14

GnomAD4 genome AF: 0.205 AC: 31158 AN: 152252 Hom.: 3494 Cov.: 33 AF XY: 0.199 AC XY: 14784 AN XY: 74426

African (AFR) AF: 0.227 AC: 9413 AN: 41542

American (AMR) AF: 0.140 AC: 2144 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 611 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5190

South Asian (SAS) AF: 0.127 AC: 612 AN: 4822

European-Finnish (FIN) AF: 0.194 AC: 2061 AN: 10604

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.231 AC: 15719 AN: 68000

Other (OTH) AF: 0.184 AC: 389 AN: 2116

Alfa AF: 0.224 Hom.: 1369

Bravo AF: 0.201

Asia WGS AF: 0.0740 AC: 256 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Bardet-Biedl syndrome 12 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.9
DANN	Benign	0.75
PhyloP100		0.45
PromoterAI		0.11	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs309358; hg19: chr4-123653926;