rs309370

Variant names:

• chr4-122743049-G-A
• rs309370
• NM_152618.3:c.1157G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-122743049-G-A
• chr4-122743049-G-C
• chr4-122743049-G-T

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.1157G>A​(p.Arg386Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,613,888 control chromosomes in the GnomAD database, including 116,672 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R386W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.42 (14660 hom., cov: 33)
  • Exomes 𝑓: 0.36 (102012 hom.)
• Consequence: BBS12 NM_152618.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0820
• Publications: 48 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.769768E-6).
• BP6: Variant 4-122743049-G-A is Benign according to our data. Variant chr4-122743049-G-A is described in ClinVar as Benign. ClinVar VariationId is 166725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 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.1157G>A	p.Arg386Gln	missense	Exon 2 of 2	NP_689831.2
	BBS12	NM_001178007.2		c.1157G>A	p.Arg386Gln	missense	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.1157G>A	p.Arg386Gln	missense	Exon 2 of 2	ENSP00000319062.3	Q6ZW61
	BBS12	ENST00000542236.5	TSL:2	c.1157G>A	p.Arg386Gln	missense	Exon 3 of 3	ENSP00000438273.1	Q6ZW61

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64410 AN: 152020 Hom.: 14629 Cov.: 33

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.467

Gnomad FIN AF: 0.276

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.412 AC: 103503 AN: 251214 AF XY: 0.408

Gnomad AFR exome AF: 0.563

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.365

Gnomad EAS exome AF: 0.663

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.340

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.365 AC: 533043 AN: 1461750 Hom.: 102012 Cov.: 60 AF XY: 0.367 AC XY: 267119 AN XY: 727168

African (AFR) AF: 0.561 AC: 18788 AN: 33474

American (AMR) AF: 0.487 AC: 21794 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9482 AN: 26136

East Asian (EAS) AF: 0.672 AC: 26664 AN: 39698

South Asian (SAS) AF: 0.468 AC: 40365 AN: 86256

European-Finnish (FIN) AF: 0.292 AC: 15572 AN: 53392

Middle Eastern (MID) AF: 0.404 AC: 2331 AN: 5768

European-Non Finnish (NFE) AF: 0.337 AC: 374291 AN: 1111912

Other (OTH) AF: 0.393 AC: 23756 AN: 60394

GnomAD4 genome AF: 0.424 AC: 64501 AN: 152138 Hom.: 14660 Cov.: 33 AF XY: 0.425 AC XY: 31587 AN XY: 74374

African (AFR) AF: 0.561 AC: 23262 AN: 41490

American (AMR) AF: 0.461 AC: 7047 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1242 AN: 3472

East Asian (EAS) AF: 0.647 AC: 3348 AN: 5178

South Asian (SAS) AF: 0.467 AC: 2249 AN: 4820

European-Finnish (FIN) AF: 0.276 AC: 2914 AN: 10574

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.339 AC: 23072 AN: 67990

Other (OTH) AF: 0.421 AC: 889 AN: 2112

Alfa AF: 0.381 Hom.: 35697

Bravo AF: 0.446

TwinsUK AF: 0.333 AC: 1234

ALSPAC AF: 0.329 AC: 1269

ESP6500AA AF: 0.563 AC: 2479

ESP6500EA AF: 0.338 AC: 2903

ExAC AF: 0.414 AC: 50226

Asia WGS AF: 0.594 AC: 2063 AN: 3478

EpiCase AF: 0.341

EpiControl AF: 0.339

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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.1
DANN	Benign	0.76
DEOGEN2	Benign	0.078	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0000078	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.082
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.065
Sift	Benign	0.57	T
Sift4G	Benign	0.52	T
Polyphen		0.0030	B
Vest4		0.019
MPC		0.097
ClinPred		0.0012	T
GERP RS		0.34
Varity_R		0.030
gMVP		0.28
Mutation Taster		=99/1	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: rs309370; hg19: chr4-123664204; COSMIC: COSV58563061; COSMIC: COSV58563061;