4-122743272-G-C

Variant names:

• chr4-122743272-G-C
• rs13135766
• NM_152618.3:c.1380G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152618.3(BBS12):​c.1380G>C​(p.Val460Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 1,614,036 control chromosomes in the GnomAD database, including 38,147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V460V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2503 hom., cov: 33)
  • Exomes 𝑓: 0.21 (35644 hom.)
• Consequence: BBS12 NM_152618.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.20
• Publications: 16 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, Myriad Women’s Health, G2P, Ambry Genetics
• BBS12-related ciliopathy

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 4-122743272-G-C is Benign according to our data. Variant chr4-122743272-G-C is described in ClinVar as Benign. ClinVar VariationId is 166726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 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.1380G>C	p.Val460Val	synonymous	Exon 2 of 2	NP_689831.2
	BBS12	NM_001178007.2		c.1380G>C	p.Val460Val	synonymous	Exon 3 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.1380G>C	p.Val460Val	synonymous	Exon 2 of 2	ENSP00000319062.3	Q6ZW61
	BBS12	ENST00000542236.5	TSL:2	c.1380G>C	p.Val460Val	synonymous	Exon 3 of 3	ENSP00000438273.1	Q6ZW61

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24179 AN: 152104 Hom.: 2502 Cov.: 33

Gnomad AFR AF: 0.0602

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.174

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.154

GnomAD2 exomes AF: 0.168 AC: 42185 AN: 251398 AF XY: 0.174

Gnomad AFR exome AF: 0.0575

Gnomad AMR exome AF: 0.0841

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.235

Gnomad OTH exome AF: 0.185

GnomAD4 exome AF: 0.212 AC: 310389 AN: 1461814 Hom.: 35644 Cov.: 70 AF XY: 0.212 AC XY: 154046 AN XY: 727218

African (AFR) AF: 0.0572 AC: 1915 AN: 33480

American (AMR) AF: 0.0887 AC: 3966 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 4490 AN: 26136

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39700

South Asian (SAS) AF: 0.144 AC: 12387 AN: 86256

European-Finnish (FIN) AF: 0.205 AC: 10958 AN: 53408

Middle Eastern (MID) AF: 0.177 AC: 1019 AN: 5768

European-Non Finnish (NFE) AF: 0.238 AC: 264337 AN: 1111948

Other (OTH) AF: 0.187 AC: 11299 AN: 60396

GnomAD4 genome AF: 0.159 AC: 24178 AN: 152222 Hom.: 2503 Cov.: 33 AF XY: 0.154 AC XY: 11483 AN XY: 74424

African (AFR) AF: 0.0600 AC: 2496 AN: 41566

American (AMR) AF: 0.126 AC: 1930 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 602 AN: 3466

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

South Asian (SAS) AF: 0.133 AC: 639 AN: 4822

European-Finnish (FIN) AF: 0.195 AC: 2059 AN: 10586

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15920 AN: 67978

Other (OTH) AF: 0.152 AC: 320 AN: 2112

Alfa AF: 0.169 Hom.: 863

Bravo AF: 0.148

Asia WGS AF: 0.0670 AC: 232 AN: 3478

EpiCase AF: 0.227

EpiControl AF: 0.225

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Bardet-Biedl syndrome 12 (3)
-	-	3	not specified (3)
-	-	2	Bardet-Biedl syndrome 1 (2)
-	-	2	not provided (2)
-	-	1	Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.1
DANN	Benign	0.75
PhyloP100		2.2
Mutation Taster		=86/14	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: rs13135766; hg19: chr4-123664427; COSMIC: COSV58561959; COSMIC: COSV58561959;