7-33146272-G-C

Variant names:

• chr7-33146272-G-C
• rs746340993
• NM_198428.3:c.20G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001348038.3(BBS9):​c.-258G>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS9 NM_001348038.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.39
• Publications: 2 publications found

Genes affected

BBS9 (HGNC:30000): (Bardet-Biedl syndrome 9) This gene is downregulated by parathyroid hormone in osteoblastic cells, and therefore is thought to be involved in parathyroid hormone action in bones. The exact function of this gene has not yet been determined. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jan 2017]

BBS9 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• BBS9-related ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348038.3. 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
	BBS9	NM_198428.3	MANE Select	c.20G>C	p.Arg7Pro	missense	Exon 2 of 23	NP_940820.1	Q3SYG4-1
	BBS9	NM_001348038.3		c.-258G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 23	NP_001334967.1
	BBS9	NM_001348039.3		c.-258G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	NP_001334968.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	ENST00000242067.11	TSL:1 MANE Select	c.20G>C	p.Arg7Pro	missense	Exon 2 of 23	ENSP00000242067.6	Q3SYG4-1
	BBS9	ENST00000433714.5	TSL:1	n.20G>C		non_coding_transcript_exon	Exon 2 of 24	ENSP00000412159.1	F8WCG5
	BBS9	ENST00000673431.1		c.-116G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	ENSP00000500552.1	A0A5F9ZHP5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Bardet-Biedl syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.4
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.56		Loss of MoRF binding (P = 3e-04)
MVP		0.97
MPC		0.46
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.011	Neutral
Varity_R		0.98
gMVP		0.86
Mutation Taster		=214/86	polymorphism

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: rs746340993; hg19: chr7-33185884;