rs773109542

Variant names:

• chr15-72686228-A-G
• rs773109542
• NM_033028.5:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_033028.5(BBS4):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,412,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BBS4 NM_033028.5 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.15
• Publications: 1 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]

HIGD2B (HGNC:26984): (HIG1 hypoxia inducible domain family member 2B) Predicted to be involved in mitochondrial respirasome assembly. Predicted to be integral component of membrane. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 44 pathogenic variants. Next in-frame start position is after 173 codons. Genomic position: 72724585. Lost 0.331 part of the original CDS.
• PS1: Another start lost variant in NM_033028.5 (BBS4) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-72686228-A-G is Pathogenic according to our data. Variant chr15-72686228-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 886465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	NM_033028.5	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 16	NP_149017.2
	BBS4	NM_001320665.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 15	NP_001307594.1	H3BSL2
	BBS4	NM_001252678.2		c.-469A>G		5_prime_UTR	Exon 1 of 15	NP_001239607.1	Q96RK4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS4	ENST00000268057.9	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 16	ENSP00000268057.4	Q96RK4-1
	BBS4	ENST00000395205.7	TSL:1	c.-464A>G		5_prime_UTR	Exon 1 of 15	ENSP00000378631.3	Q96RK4-3
	BBS4	ENST00000566400.6	TSL:1	c.-469A>G		5_prime_UTR	Exon 1 of 15	ENSP00000456759.2	H3BSL3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000113 AC: 2 AN: 176590 AF XY: 0.0000106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000371

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000210

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1412324 Hom.: 0 Cov.: 31 AF XY: 0.00000287 AC XY: 2 AN XY: 697916

African (AFR) AF: 0.00 AC: 0 AN: 32300

American (AMR) AF: 0.0000265 AC: 1 AN: 37786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25304

East Asian (EAS) AF: 0.00 AC: 0 AN: 37052

South Asian (SAS) AF: 0.00 AC: 0 AN: 80112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4508

European-Non Finnish (NFE) AF: 9.20e-7 AC: 1 AN: 1087440

Other (OTH) AF: 0.0000171 AC: 1 AN: 58452

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000851 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Bardet-Biedl syndrome (2)
1	-	-	Bardet-Biedl syndrome 4 (1)
1	-	-	BBS4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.80	T
PhyloP100		3.2
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.35
Sift	Benign	0.12	T
Sift4G	Uncertain	0.058	T
Polyphen		0.0070	B
Vest4		0.81
MutPred		0.99		Loss of MoRF binding (P = 0.1006)
MVP		0.69
ClinPred		0.97	D
GERP RS		2.5
PromoterAI		-0.48	Neutral
Varity_R		0.43
gMVP		0.36
Mutation Taster		=33/167	disease causing

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: rs773109542; hg19: chr15-72978569;