rs35194418

Variant names:

• chr4-121861659-G-A
• rs35194418
• NM_176824.3:c.186C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-121861659-G-A
• chr4-121861659-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_176824.3(BBS7):​c.186C>T​(p.Pro62Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,613,080 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P62P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0062 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (5 hom.)
• Consequence: BBS7 NM_176824.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.51
• Publications: 1 publications found

Genes affected

BBS7 (HGNC:18758): (Bardet-Biedl syndrome 7) This gene encodes one of eight proteins that form the BBSome complex containing BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9 and BBIP10. The BBSome complex is believed to recruit Rab8(GTP) to the primary cilium and promote ciliogenesis. The BBSome complex assembly is mediated by a complex composed of three chaperonin-like BBS proteins (BBS6, BBS10, and BBS12) and CCT/TRiC family chaperonins. Mutations in this gene are implicated in Bardet-Biedl syndrome, a genetic disorder whose symptoms include obesity, retinal degeneration, polydactyly and nephropathy; however, mutations in this gene and the BBS8 gene are thought to play a minor role and mutations in chaperonin-like BBS genes are found to be a major contributor to disease development in a multiethnic Bardet-Biedl syndrome patient population. Two transcript variants encoding distinct isoforms have been identified for this gene.[provided by RefSeq, Oct 2014]

BBS7 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• BBS7-related 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 4-121861659-G-A is Benign according to our data. Variant chr4-121861659-G-A is described in ClinVar as Benign. ClinVar VariationId is 262920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.51 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00617 (936/151742) while in subpopulation AFR AF = 0.0203 (839/41352). AF 95% confidence interval is 0.0192. There are 7 homozygotes in GnomAd4. There are 450 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176824.3. 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
	BBS7	NM_176824.3	MANE Select	c.186C>T	p.Pro62Pro	synonymous	Exon 4 of 19	NP_789794.1	Q8IWZ6-1
	BBS7	NM_018190.4		c.186C>T	p.Pro62Pro	synonymous	Exon 4 of 18	NP_060660.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS7	ENST00000264499.9	TSL:1 MANE Select	c.186C>T	p.Pro62Pro	synonymous	Exon 4 of 19	ENSP00000264499.4	Q8IWZ6-1
	BBS7	ENST00000506636.1	TSL:1	c.186C>T	p.Pro62Pro	synonymous	Exon 4 of 18	ENSP00000423626.1	Q8IWZ6-2
	BBS7	ENST00000888033.1		c.186C>T	p.Pro62Pro	synonymous	Exon 4 of 19	ENSP00000558092.1

Frequencies

GnomAD3 genomes AF: 0.00616 AC: 934 AN: 151624 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00309

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000952

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000427

Gnomad OTH AF: 0.00865

GnomAD2 exomes AF: 0.00179 AC: 450 AN: 251110 AF XY: 0.00140

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000711 AC: 1039 AN: 1461338 Hom.: 5 Cov.: 31 AF XY: 0.000604 AC XY: 439 AN XY: 726962

African (AFR) AF: 0.0182 AC: 610 AN: 33460

American (AMR) AF: 0.00204 AC: 91 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39666

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53378

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000182 AC: 202 AN: 1111654

Other (OTH) AF: 0.00192 AC: 116 AN: 60362

GnomAD4 genome AF: 0.00617 AC: 936 AN: 151742 Hom.: 7 Cov.: 32 AF XY: 0.00607 AC XY: 450 AN XY: 74120

African (AFR) AF: 0.0203 AC: 839 AN: 41352

American (AMR) AF: 0.00309 AC: 47 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.0000952 AC: 1 AN: 10500

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000427 AC: 29 AN: 67932

Other (OTH) AF: 0.00856 AC: 18 AN: 2102

Alfa AF: 0.00256 Hom.: 2

Bravo AF: 0.00692

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.43
DANN	Benign	0.57
PhyloP100		-1.5
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs35194418; hg19: chr4-122782814;