rs147202164

Positions:

• chr15-72735954-A-T

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 262136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72735954-A-T is described in Lovd as [Benign]. Variant chr15-72735954-A-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS4	NM_033028.5	c.1236A>T	p.Glu412Asp	missense_variant	14/16	ENST00000268057.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS4	ENST00000268057.9	c.1236A>T	p.Glu412Asp	missense_variant	14/16	1	NM_033028.5	P1

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

GnomAD3 exomes AF: 0.00166 AC: 417 AN: 251412 Hom.: 4 AF XY: 0.00205 AC XY: 278 AN XY: 135872

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 SAS exome AF: 0.00715

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

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00728

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000851

Gnomad4 OTH exome AF: 0.00142

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

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.000947

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

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	BBS4: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Bardet-Biedl syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 13, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.85	D;D;D;D
PrimateAI	Benign	0.42	T
REVEL	Benign	0.12
Sift4G	Benign	0.61	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs147202164; hg19: chr15-73028295;