ENST00000425508.6:c.-34_-24+2delAAATGGACAAGGT

Variant names:

• chr7-33146353-GAAATGGACAAGGT-G
• rs869025208
• ENST00000425508.6:c.-34_-24+2delAAATGGACAAGGT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The ENST00000425508.6(BBS9):​c.-34_-24+2delAAATGGACAAGGT variant causes a splice donor, 5 prime UTR, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BBS9 ENST00000425508.6 splice_donor, 5_prime_UTR, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.47
• Publications: 0 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 3 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03858521 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 7-33146353-GAAATGGACAAGGT-G is Pathogenic according to our data. Variant chr7-33146353-GAAATGGACAAGGT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 217437.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000425508.6. 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.104_112+4delATGGACAAGGTAA	p.Gly36_Asp38del	splice_donor conservative_inframe_deletion splice_region intron	Exon 2 of 23	NP_940820.1	Q3SYG4-1
	BBS9	NM_001348038.3		c.-174_-166+4delATGGACAAGGTAA		splice_region	Exon 2 of 23	NP_001334967.1
	BBS9	NM_001348039.3		c.-174_-166+4delATGGACAAGGTAA		splice_region	Exon 2 of 22	NP_001334968.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	ENST00000425508.6	TSL:1	c.-34_-24+2delAAATGGACAAGGT		splice_region	Exon 1 of 9	ENSP00000405151.2	Q3SYG4-5
	BBS9	ENST00000242067.11	TSL:1 MANE Select	c.102_112+2delAAATGGACAAGGT	p.Asn35LysfsTer2	frameshift splice_donor splice_region intron	Exon 2 of 23	ENSP00000242067.6	Q3SYG4-1
	BBS9	ENST00000425508.6	TSL:1	c.-34_-24+2delAAATGGACAAGGT		splice_donor 5_prime_UTR intron	Exon 1 of 9	ENSP00000405151.2	Q3SYG4-5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Bardet-Biedl syndrome 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=70/230	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869025208; hg19: chr7-33185965;