rs111442398

Positions:

• chr4-121843997-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP4_Strong BS1_Supporting BS2

The ENST00000264499.9(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 ENST00000264499.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 6.19

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.04046455).
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BBS7	NM_176824.3	c.1235A>G	p.Asp412Gly	missense_variant	12/19	ENST00000264499.9	NP_789794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BBS7	ENST00000264499.9	c.1235A>G	p.Asp412Gly	missense_variant	12/19	1	NM_176824.3	ENSP00000264499	P1
BBS7	ENST00000506636.1	c.1235A>G	p.Asp412Gly	missense_variant	12/18	1		ENSP00000423626

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

GnomAD3 exomes AF: 0.00149 AC: 334 AN: 224248 Hom.: 1 AF XY: 0.00146 AC XY: 176 AN XY: 120592

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 SAS exome AF: 0.000396

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

Gnomad4 AFR exome AF: 0.000424

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00501

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.000229

Gnomad4 NFE exome AF: 0.00241

Gnomad4 OTH exome AF: 0.00179

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

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00243 Hom.: 0

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	BBS7: PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in the heterozygous state in a patient with retinal dystrophy, postaxial polydactyly, and intellectual disability who also harbored a homozgyous variant in the BBS1 gene (Perea-Romero et al., 2022); This variant is associated with the following publications: (PMID: 25533962, 31376382, 35835773) -

Bardet-Biedl syndrome 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

Bardet-Biedl syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.040	T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.013	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs111442398; hg19: chr4-122765152; COSMIC: COSV52659143;