15-72735137-T-C

Variant names:

• chr15-72735137-T-C
• rs2277598
• NM_033028.5:c.1061T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033028.5(BBS4):​c.1061T>C​(p.Ile354Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.605 in 1,612,062 control chromosomes in the GnomAD database, including 303,685 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23091 hom., cov: 32)
  • Exomes 𝑓: 0.61 (280594 hom.)
• Consequence: BBS4 NM_033028.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.248
• Publications: 56 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
• 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=2.0739299E-6).
• BP6: Variant 15-72735137-T-C is Benign according to our data. Variant chr15-72735137-T-C is described in ClinVar as Benign. ClinVar VariationId is 21734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

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.1061T>C	p.Ile354Thr	missense	Exon 13 of 16	NP_149017.2
	BBS4	NM_001320665.2		c.992T>C	p.Ile331Thr	missense	Exon 12 of 15	NP_001307594.1
	BBS4	NM_001252678.2		c.545T>C	p.Ile182Thr	missense	Exon 12 of 15	NP_001239607.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.1061T>C	p.Ile354Thr	missense	Exon 13 of 16	ENSP00000268057.4
	BBS4	ENST00000395205.7	TSL:1	c.545T>C	p.Ile182Thr	missense	Exon 12 of 15	ENSP00000378631.3
	BBS4	ENST00000566400.6	TSL:1	c.545T>C	p.Ile182Thr	missense	Exon 12 of 15	ENSP00000456759.2

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80060 AN: 151870 Hom.: 23108 Cov.: 32

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.697

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.586

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.555

GnomAD2 exomes AF: 0.573 AC: 144029 AN: 251154 AF XY: 0.587

Gnomad AFR exome AF: 0.306

Gnomad AMR exome AF: 0.497

Gnomad ASJ exome AF: 0.674

Gnomad EAS exome AF: 0.248

Gnomad FIN exome AF: 0.662

Gnomad NFE exome AF: 0.652

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.613 AC: 895113 AN: 1460074 Hom.: 280594 Cov.: 37 AF XY: 0.616 AC XY: 447589 AN XY: 726432

African (AFR) AF: 0.307 AC: 10266 AN: 33462

American (AMR) AF: 0.497 AC: 22232 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 17620 AN: 26114

East Asian (EAS) AF: 0.229 AC: 9095 AN: 39684

South Asian (SAS) AF: 0.601 AC: 51796 AN: 86226

European-Finnish (FIN) AF: 0.662 AC: 35322 AN: 53378

Middle Eastern (MID) AF: 0.632 AC: 3594 AN: 5690

European-Non Finnish (NFE) AF: 0.639 AC: 709763 AN: 1110494

Other (OTH) AF: 0.587 AC: 35425 AN: 60336

GnomAD4 genome AF: 0.527 AC: 80052 AN: 151988 Hom.: 23091 Cov.: 32 AF XY: 0.530 AC XY: 39337 AN XY: 74266

African (AFR) AF: 0.311 AC: 12893 AN: 41468

American (AMR) AF: 0.530 AC: 8095 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2330 AN: 3462

East Asian (EAS) AF: 0.245 AC: 1268 AN: 5170

South Asian (SAS) AF: 0.585 AC: 2817 AN: 4814

European-Finnish (FIN) AF: 0.658 AC: 6934 AN: 10540

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.644 AC: 43723 AN: 67944

Other (OTH) AF: 0.549 AC: 1159 AN: 2110

Alfa AF: 0.600 Hom.: 109140

Bravo AF: 0.508

TwinsUK AF: 0.642 AC: 2382

ALSPAC AF: 0.648 AC: 2497

ESP6500AA AF: 0.322 AC: 1416

ESP6500EA AF: 0.640 AC: 5504

ExAC AF: 0.573 AC: 69585

Asia WGS AF: 0.395 AC: 1378 AN: 3478

EpiCase AF: 0.647

EpiControl AF: 0.653

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Bardet-Biedl syndrome (2)
-	-	2	Bardet-Biedl syndrome 4 (2)
-	-	2	not provided (2)
-	-	1	Bardet-Biedl syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	8.3
DANN	Benign	0.66
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0000021	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.25
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.19
Sift	Benign	0.40	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.066
MPC		0.012
ClinPred		0.0091	T
GERP RS		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.063
gMVP		0.15
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2277598; hg19: chr15-73027478; COSMIC: COSV51438920; COSMIC: COSV51438920;