rs147202164

Variant names:

• chr15-72735954-A-T
• rs147202164
• NM_033028.5:c.1236A>T

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.1236A>T​(p.Glu412Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,614,128 control chromosomes in the GnomAD database, including 13 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (13 hom.)
• Consequence: BBS4 NM_033028.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.645
• Publications: 6 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=0.0062256753).
• BP6: Variant 15-72735954-A-T is Benign according to our data. Variant chr15-72735954-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.1236A>T	p.Glu412Asp	missense	Exon 14 of 16	NP_149017.2
	BBS4	NM_001320665.2		c.1167A>T	p.Glu389Asp	missense	Exon 13 of 15	NP_001307594.1	H3BSL2
	BBS4	NM_001252678.2		c.720A>T	p.Glu240Asp	missense	Exon 13 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.1236A>T	p.Glu412Asp	missense	Exon 14 of 16	ENSP00000268057.4	Q96RK4-1
	BBS4	ENST00000395205.7	TSL:1	c.720A>T	p.Glu240Asp	missense	Exon 13 of 15	ENSP00000378631.3	Q96RK4-3
	BBS4	ENST00000566400.6	TSL:1	c.720A>T	p.Glu240Asp	missense	Exon 13 of 15	ENSP00000456759.2	H3BSL3

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00806

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00166 AC: 417 AN: 251412 AF XY: 0.00205

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00122 AC: 1780 AN: 1461850 Hom.: 13 Cov.: 31 AF XY: 0.00142 AC XY: 1036 AN XY: 727236

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00110 AC: 49 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00728 AC: 628 AN: 86256

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53408

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5768

European-Non Finnish (NFE) AF: 0.000851 AC: 946 AN: 1111990

Other (OTH) AF: 0.00142 AC: 86 AN: 60394

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000954 AC XY: 71 AN XY: 74456

African (AFR) AF: 0.000168 AC: 7 AN: 41568

American (AMR) AF: 0.00131 AC: 20 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00807 AC: 39 AN: 4832

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68014

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000782

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00170 AC: 207

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00136

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.8
DANN	Benign	0.84
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L
PhyloP100		-0.65
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.12
Sift	Benign	0.63	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.54		Loss of helix (P = 0.079)
MVP		0.47
MPC		0.012
ClinPred		0.0081	T
GERP RS		-1.6
Varity_R		0.066
gMVP		0.12
Mutation Taster		=97/3	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: rs147202164; hg19: chr15-73028295; COSMIC: COSV107266706; COSMIC: COSV107266706;