rs111442398

Variant names:

• chr4-121843997-T-C
• rs111442398
• NM_176824.3:c.1235A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PP2 PP3 BP4_Strong BP6 BS1 BS2

The NM_176824.3(BBS7):​c.1235A>G​(p.Asp412Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,584,246 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D412Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: BBS7 NM_176824.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 6.19
• Publications: 9 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 -11 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.2326 (below the threshold of 3.09). Trascript score misZ: 1.7868 (below the threshold of 3.09). GenCC associations: The gene is linked to Bardet-Biedl syndrome, Bardet-Biedl syndrome 7, BBS7-related ciliopathy.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.04046455).
• BP6: Variant 4-121843997-T-C is Benign according to our data. Variant chr4-121843997-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 531839.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00147 (223/152178) while in subpopulation NFE AF = 0.0024 (163/68002). AF 95% confidence interval is 0.0021. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.1235A>G	p.Asp412Gly	missense	Exon 12 of 19	NP_789794.1	Q8IWZ6-1
	BBS7	NM_018190.4		c.1235A>G	p.Asp412Gly	missense	Exon 12 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.1235A>G	p.Asp412Gly	missense	Exon 12 of 19	ENSP00000264499.4	Q8IWZ6-1
	BBS7	ENST00000506636.1	TSL:1	c.1235A>G	p.Asp412Gly	missense	Exon 12 of 18	ENSP00000423626.1	Q8IWZ6-2
	BBS7	ENST00000888033.1		c.1283A>G	p.Asp428Gly	missense	Exon 12 of 19	ENSP00000558092.1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152060 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00149 AC: 334 AN: 224248 AF XY: 0.00146

Gnomad AFR exome AF: 0.000567

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00441

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000971

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.000887

GnomAD4 exome AF: 0.00207 AC: 2967 AN: 1432068 Hom.: 4 Cov.: 26 AF XY: 0.00202 AC XY: 1439 AN XY: 711796

African (AFR) AF: 0.000424 AC: 14 AN: 33022

American (AMR) AF: 0.00116 AC: 50 AN: 43190

Ashkenazi Jewish (ASJ) AF: 0.00501 AC: 128 AN: 25524

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.000394 AC: 33 AN: 83766

European-Finnish (FIN) AF: 0.000229 AC: 12 AN: 52388

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5680

European-Non Finnish (NFE) AF: 0.00241 AC: 2622 AN: 1090024

Other (OTH) AF: 0.00179 AC: 106 AN: 59142

GnomAD4 genome AF: 0.00147 AC: 223 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74406

African (AFR) AF: 0.000385 AC: 16 AN: 41518

American (AMR) AF: 0.00170 AC: 26 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00240 AC: 163 AN: 68002

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.00222 Hom.: 4

Bravo AF: 0.00164

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000911 AC: 4

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00129 AC: 156

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Bardet-Biedl syndrome (1)
-	1	-	Bardet-Biedl syndrome 7 (1)
-	-	1	BBS7-related ciliopathy (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.040	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.2
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.013	D
Polyphen		0.92	P
Vest4		0.75
MVP		0.95
MPC		0.47
ClinPred		0.032	T
GERP RS		6.1
Varity_R		0.64
gMVP		0.66
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs111442398; hg19: chr4-122765152; COSMIC: COSV52659143;