NM_033028.5:c.137A>G

Variant names:

• chr15-72709760-A-G
• rs75295839
• NM_033028.5:c.137A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_033028.5(BBS4):​c.137A>G​(p.Lys46Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00891 in 1,613,402 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K46K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (94 hom.)
• Consequence: BBS4 NM_033028.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 6.34
• Publications: 12 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008608013).
• BP6: Variant 15-72709760-A-G is Benign according to our data. Variant chr15-72709760-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196570.
• BS2: High Homozygotes in GnomAd4 at 3 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.137A>G	p.Lys46Arg	missense	Exon 3 of 16	NP_149017.2
	BBS4	NM_001320665.2		c.137A>G	p.Lys46Arg	missense	Exon 3 of 15	NP_001307594.1	H3BSL2
	BBS4	NM_001252678.2		c.-385A>G		5_prime_UTR	Exon 2 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.137A>G	p.Lys46Arg	missense	Exon 3 of 16	ENSP00000268057.4	Q96RK4-1
	BBS4	ENST00000395205.7	TSL:1	c.-380A>G		5_prime_UTR	Exon 2 of 15	ENSP00000378631.3	Q96RK4-3
	BBS4	ENST00000566400.6	TSL:1	c.-385A>G		5_prime_UTR	Exon 2 of 15	ENSP00000456759.2	H3BSL3

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 979 AN: 152152 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00995

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00687 AC: 1726 AN: 251304 AF XY: 0.00692

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00723

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00325

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00897

GnomAD4 exome AF: 0.00917 AC: 13396 AN: 1461132 Hom.: 94 Cov.: 32 AF XY: 0.00913 AC XY: 6640 AN XY: 726924

African (AFR) AF: 0.00197 AC: 66 AN: 33466

American (AMR) AF: 0.00704 AC: 315 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00995 AC: 260 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86252

European-Finnish (FIN) AF: 0.00368 AC: 196 AN: 53254

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5764

European-Non Finnish (NFE) AF: 0.0107 AC: 11908 AN: 1111490

Other (OTH) AF: 0.00863 AC: 521 AN: 60376

GnomAD4 genome AF: 0.00643 AC: 979 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74458

African (AFR) AF: 0.00207 AC: 86 AN: 41530

American (AMR) AF: 0.00811 AC: 124 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00995 AC: 677 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.00881 Hom.: 31

Bravo AF: 0.00685

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00686 AC: 833

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00992

EpiControl AF: 0.00960

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	3	not provided (4)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	Bardet-Biedl syndrome 1 (1)
-	-	1	Bardet-Biedl syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.093
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.20	T
Sift4G	Benign	0.41	T
Polyphen		0.0050	B
Vest4		0.28
MVP		0.84
MPC		0.014
ClinPred		0.016	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.47
Mutation Taster		=256/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs75295839; hg19: chr15-73002101;