rs35487251

Variant names:

• chr2-169497628-G-A
• rs35487251
• NM_152384.3:c.620G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP2 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:9
• Conservation: PhyloP100: 9.18
• Publications: 17 publications found

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]

BBS5 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine
• BBS5-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251569 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.85025 (below the threshold of 3.09). Trascript score misZ: 1.0056 (below the threshold of 3.09). GenCC associations: The gene is linked to Bardet-Biedl syndrome 5, Bardet-Biedl syndrome.
• PP3: Splicing predictors support a deleterious 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 Benign/Likely_benign. ClinVar VariationId is 96499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 86 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152384.3. 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
	BBS5	NM_152384.3	MANE Select	c.620G>A	p.Arg207His	missense splice_region	Exon 8 of 12	NP_689597.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS5	ENST00000295240.8	TSL:1 MANE Select	c.620G>A	p.Arg207His	missense splice_region	Exon 8 of 12	ENSP00000295240.3
	ENSG00000251569	ENST00000513963.1	TSL:2	c.620G>A	p.Arg207His	missense splice_region	Exon 8 of 16	ENSP00000424363.1
	BBS5	ENST00000392663.6	TSL:1	c.619-1858G>A		intron	N/A	ENSP00000376431.2

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

GnomAD2 exomes AF: 0.00656 AC: 1643 AN: 250580 AF XY: 0.00681

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 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

African (AFR) AF: 0.00147 AC: 48 AN: 32702

American (AMR) AF: 0.00300 AC: 134 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00298 AC: 77 AN: 25854

East Asian (EAS) AF: 0.00429 AC: 169 AN: 39358

South Asian (SAS) AF: 0.00626 AC: 533 AN: 85078

European-Finnish (FIN) AF: 0.0104 AC: 556 AN: 53360

Middle Eastern (MID) AF: 0.00387 AC: 22 AN: 5692

European-Non Finnish (NFE) AF: 0.00886 AC: 9559 AN: 1078514

Other (OTH) AF: 0.00573 AC: 339 AN: 59150

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

African (AFR) AF: 0.00222 AC: 92 AN: 41512

American (AMR) AF: 0.00334 AC: 51 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00289 AC: 10 AN: 3466

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5180

South Asian (SAS) AF: 0.00643 AC: 31 AN: 4824

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10570

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

European-Non Finnish (NFE) AF: 0.00859 AC: 584 AN: 67974

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00670 Hom.: 11

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.4	L
PhyloP100		9.2
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	0.12	T
Sift4G	Benign	0.13	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
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.84
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs35487251; hg19: chr2-170354138; COSMIC: COSV54754810; COSMIC: COSV54754810;