rs143191074

Positions:

• chr2-169493802-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_152384.3(BBS5):​c.584A>G​(p.Asp195Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,611,756 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (46 hom.)
• Consequence: BBS5 NM_152384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 9.32

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011274219).
• BP6: Variant 2-169493802-A-G is Benign according to our data. Variant chr2-169493802-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96498.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00183 (279/152352) while in subpopulation AMR AF= 0.0156 (239/15306). AF 95% confidence interval is 0.014. There are 4 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS5	NM_152384.3	c.584A>G	p.Asp195Gly	missense_variant	7/12	ENST00000295240.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS5	ENST00000295240.8	c.584A>G	p.Asp195Gly	missense_variant	7/12	1	NM_152384.3	P1
BBS5	ENST00000392663.6	c.584A>G	p.Asp195Gly	missense_variant	7/11	1
BBS5	ENST00000443151.1	c.*306A>G		3_prime_UTR_variant, NMD_transcript_variant	5/6	5

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152234 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00634 AC: 1593 AN: 251228 Hom.: 34 AF XY: 0.00440 AC XY: 598 AN XY: 135806

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.0448

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00132 AC: 1933 AN: 1459404 Hom.: 46 Cov.: 29 AF XY: 0.00104 AC XY: 754 AN XY: 726154

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.0410

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152352 Hom.: 4 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74506

Gnomad4 AFR AF: 0.000601

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000519 Hom.: 0

Bravo AF: 0.00413

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00450 AC: 546

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2016

The D195G variant in the BBS5 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D195G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Aspartic Acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D195G as a variant of uncertain significance. -

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	Uncertain	0.34
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0070	D;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.51	P;B;.
Vest4		0.66
MVP		0.88
MPC		0.64
ClinPred		0.027	T
GERP RS		5.8
Varity_R		0.58
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs143191074; hg19: chr2-170350312; COSMIC: COSV54753568; COSMIC: COSV54753568;