rs35487251

chr2-169497628-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_152384.3(BBS5):c.620G>A(p.Arg207His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00785 in 1,576,430 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R207C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (86 hom.)
• Consequence: BBS5 NM_152384.3 missense, splice_region
• Scores: Splicing: ADA: 0.9811
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 9.18

Genes affected

BBS5 (HGNC:970): (Bardet-Biedl syndrome 5) This gene encodes a protein that has been directly linked to Bardet-Biedl syndrome. The primary features of this syndrome include retinal dystrophy, obesity, polydactyly, renal abnormalities and learning disabilities. Experimentation in non-human eukaryotes suggests that this gene is expressed in ciliated cells and that it is required for the formation of cilia. Alternate transcriptional splice variants have been observed but have not been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 2-169497628-G-A is Benign according to our data. Variant chr2-169497628-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-169497628-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00612 (931/152124) while in subpopulation NFE AF= 0.00859 (584/67974). AF 95% confidence interval is 0.00801. There are 1 homozygotes in gnomad4. There are 459 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS5	NM_152384.3	c.620G>A	p.Arg207His	missense_variant, splice_region_variant	8/12	ENST00000295240.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS5	ENST00000295240.8	c.620G>A	p.Arg207His	missense_variant, splice_region_variant	8/12	1	NM_152384.3	P1
BBS5	ENST00000392663.6	c.619-1858G>A		intron_variant		1
BBS5	ENST00000443151.1	c.*342G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 931 AN: 152006 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00222

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00859

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00656 AC: 1643 AN: 250580 Hom.: 11 AF XY: 0.00681 AC XY: 923 AN XY: 135514

Gnomad AFR exome AF: 0.00242

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.00612

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00884

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00803 AC: 11437 AN: 1424306 Hom.: 86 Cov.: 26 AF XY: 0.00798 AC XY: 5667 AN XY: 710514

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00298

Gnomad4 EAS exome AF: 0.00429

Gnomad4 SAS exome AF: 0.00626

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.00886

Gnomad4 OTH exome AF: 0.00573

GnomAD4 genome AF: 0.00612 AC: 931 AN: 152124 Hom.: 1 Cov.: 32 AF XY: 0.00617 AC XY: 459 AN XY: 74374

Gnomad4 AFR AF: 0.00222

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.00859

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00698 Hom.: 9

Bravo AF: 0.00512

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.00828 AC: 71

ExAC AF: 0.00640 AC: 777

Asia WGS AF: 0.00289 AC: 10 AN: 3472

EpiCase AF: 0.00765

EpiControl AF: 0.00735

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 25, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2022	Variant summary: BBS5 c.620G>A (p.Arg207His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0066 in 250580 control chromosomes in the gnomAD database, including 11 homozygotes. The observed variant frequency is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS5 causing Bardet-Biedl Syndrome phenotype (0.00062), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	BBS5: BP4, BS2 -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.23
Sift	Benign	0.12	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.83	P;.
Vest4		0.56
MVP		0.86
MPC		0.61
ClinPred		0.012	T
GERP RS		5.7
Varity_R		0.16
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.11		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: rs35487251; hg19: chr2-170354138; COSMIC: COSV54754810; COSMIC: COSV54754810;