rs34620165

Variant names:

• chr15-72731341-G-A
• rs34620165
• NM_033028.5:c.748G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-72731341-G-A
• chr15-72731341-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_033028.5(BBS4):​c.748G>A​(p.Gly250Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000765 in 1,613,980 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts 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. G250E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (7 hom., cov: 29)
  • Exomes 𝑓: 0.00041 (4 hom.)
• Consequence: BBS4 NM_033028.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.98
• Publications: 1 publications found

Genes affected

BBS4 (HGNC:969): (Bardet-Biedl syndrome 4) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse. The similar phenotypes exhibited by mutations in BBS gene family members are likely due to the protein's shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene has sequence similarity to O-linked N-acetylglucosamine (O-GlcNAc) transferases in plants and archaebacteria and in human forms a multi-protein "BBSome" complex with seven other BBS proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

BBS4 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• BBS4-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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010049701).
• BP6: Variant 15-72731341-G-A is Benign according to our data. Variant chr15-72731341-G-A is described in ClinVar as Benign. ClinVar VariationId is 262142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033028.5. 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
	BBS4	NM_033028.5	MANE Select	c.748G>A	p.Gly250Arg	missense	Exon 11 of 16	NP_149017.2
	BBS4	NM_001320665.2		c.679G>A	p.Gly227Arg	missense	Exon 10 of 15	NP_001307594.1	H3BSL2
	BBS4	NM_001252678.2		c.232G>A	p.Gly78Arg	missense	Exon 10 of 15	NP_001239607.1	Q96RK4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.748G>A	p.Gly250Arg	missense	Exon 11 of 16	ENSP00000268057.4	Q96RK4-1
	BBS4	ENST00000395205.7	TSL:1	c.232G>A	p.Gly78Arg	missense	Exon 10 of 15	ENSP00000378631.3	Q96RK4-3
	BBS4	ENST00000566400.6	TSL:1	c.232G>A	p.Gly78Arg	missense	Exon 10 of 15	ENSP00000456759.2	H3BSL3

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 637 AN: 151972 Hom.: 7 Cov.: 29

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00112 AC: 282 AN: 251486 AF XY: 0.000714

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000408 AC: 596 AN: 1461890 Hom.: 4 Cov.: 31 AF XY: 0.000309 AC XY: 225 AN XY: 727248

African (AFR) AF: 0.0154 AC: 515 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112012

Other (OTH) AF: 0.000695 AC: 42 AN: 60396

GnomAD4 genome AF: 0.00419 AC: 638 AN: 152090 Hom.: 7 Cov.: 29 AF XY: 0.00413 AC XY: 307 AN XY: 74330

African (AFR) AF: 0.0149 AC: 617 AN: 41460

American (AMR) AF: 0.000982 AC: 15 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00149 Hom.: 6

Bravo AF: 0.00497

ESP6500AA AF: 0.0166 AC: 73

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00146 AC: 177

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	2.0	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.64
Sift	Benign	0.10	T
Sift4G	Benign	0.35	T
Polyphen		0.92	P
Vest4		0.73
MutPred		0.51		Gain of solvent accessibility (P = 0.0674)
MVP		0.83
MPC		0.014
ClinPred		0.093	T
GERP RS		4.9
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.78
Mutation Taster		=82/18	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: rs34620165; hg19: chr15-73023682; COSMIC: COSV99166382; COSMIC: COSV99166382;