15-72736927-A-G

Variant names:

• chr15-72736927-A-G
• rs2277596
• NM_033028.5:c.1414A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_033028.5(BBS4):​c.1414A>G​(p.Met472Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,614,200 control chromosomes in the GnomAD database, including 2 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. M472L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (2 hom.)
• Consequence: BBS4 NM_033028.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:5
• Conservation: PhyloP100: 9.16
• Publications: 11 publications found

Genes affected

BBS4 (HGNC:969): (Bardet-Biedl syndrome 4) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse. The similar phenotypes exhibited by mutations in BBS gene family members are likely due to the protein's shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene has sequence similarity to O-linked N-acetylglucosamine (O-GlcNAc) transferases in plants and archaebacteria and in human forms a multi-protein "BBSome" complex with seven other BBS proteins. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

BBS4 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011805832).
• BP6: Variant 15-72736927-A-G is Benign according to our data. Variant chr15-72736927-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 143161.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033028.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	NM_033028.5	MANE Select	c.1414A>G	p.Met472Val	missense	Exon 15 of 16	NP_149017.2
	BBS4	NM_001320665.2		c.1345A>G	p.Met449Val	missense	Exon 14 of 15	NP_001307594.1
	BBS4	NM_001252678.2		c.898A>G	p.Met300Val	missense	Exon 14 of 15	NP_001239607.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.1414A>G	p.Met472Val	missense	Exon 15 of 16	ENSP00000268057.4
	BBS4	ENST00000395205.7	TSL:1	c.898A>G	p.Met300Val	missense	Exon 14 of 15	ENSP00000378631.3
	BBS4	ENST00000566400.6	TSL:1	c.898A>G	p.Met300Val	missense	Exon 14 of 15	ENSP00000456759.2

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00943

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000672 AC: 169 AN: 251306 AF XY: 0.000655

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00794

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000398 AC: 582 AN: 1461884 Hom.: 2 Cov.: 32 AF XY: 0.000393 AC XY: 286 AN XY: 727244

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00995 AC: 395 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000129 AC: 144 AN: 1112006

Other (OTH) AF: 0.000364 AC: 22 AN: 60396

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74498

African (AFR) AF: 0.000144 AC: 6 AN: 41576

American (AMR) AF: 0.000131 AC: 2 AN: 15298

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

East Asian (EAS) AF: 0.00945 AC: 49 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000560 Hom.: 0

Bravo AF: 0.000529

ExAC AF: 0.000651 AC: 79

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bardet-Biedl syndrome 4 Pathogenic:1 Uncertain:1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: reference population

not provided Uncertain:1 Benign:1

Oct 11, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect, as a zebrafish embryo assay suggests a null mutation (Zaghloul et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in two individuals with nephronophthisis-related ciliopathy, however no second BBS4 variant was identified (Kang et al., 2016); Observed in mother and daughter with Bardet-Biedl syndrome who were both also homozygous for a variant in the BBS1 gene (Beales et al., 2003); This variant is associated with the following publications: (PMID: 15224652, 20498079, 12677556, 26260382, 27491411, 23142271, 12872256)

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BBS4 c.1414A>G (p.Met472Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 251306 control chromosomes, predominantly at a frequency of 0.0079 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BBS4 causing Bardet-Biedl Syndrome phenotype (0.00069). Although c.1414A>G has been reported in the literature, no penetrant association of this variant has been reported in individuals affected with Bardet-Biedl Syndrome (example, Beales_2003). These report(s) do not provide unequivocal conclusions about association of the variant with Bardet-Biedl Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 12677556). ClinVar contains an entry for this variant (Variation ID: 143161). Based on the evidence outlined above, the variant was classified as likely benign.

Bardet-Biedl syndrome Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.073	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.16	T
Polyphen		0.15	B
Vest4		0.81
MVP		0.86
MPC		0.013
ClinPred		0.086	T
GERP RS		6.0
Varity_R		0.71
gMVP		0.43
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2277596; hg19: chr15-73029268; COSMIC: COSV51438043; COSMIC: COSV51438043;