7-33257348-C-T

Variant names:

• chr7-33257348-C-T
• rs35440033
• NM_198428.3:c.555C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_198428.3(BBS9):​c.555C>T​(p.Ala185Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,902 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A185A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (20 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (14 hom.)
• Consequence: BBS9 NM_198428.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.115
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 7-33257348-C-T is Benign according to our data. Variant chr7-33257348-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 242249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0081 (1233/152196) while in subpopulation AFR AF = 0.0284 (1178/41524). AF 95% confidence interval is 0.027. There are 20 homozygotes in GnomAd4. There are 591 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198428.3. 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.555C>T	p.Ala185Ala	synonymous	Exon 6 of 23	NP_940820.1	Q3SYG4-1
	BBS9	NM_001348041.4		c.555C>T	p.Ala185Ala	synonymous	Exon 6 of 23	NP_001334970.1	A0A5F9ZH14
	BBS9	NM_001348036.1		c.555C>T	p.Ala185Ala	synonymous	Exon 6 of 23	NP_001334965.1	Q3SYG4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	ENST00000242067.11	TSL:1 MANE Select	c.555C>T	p.Ala185Ala	synonymous	Exon 6 of 23	ENSP00000242067.6	Q3SYG4-1
	BBS9	ENST00000425508.6	TSL:1	c.420C>T	p.Ala140Ala	synonymous	Exon 5 of 9	ENSP00000405151.2	Q3SYG4-5
	BBS9	ENST00000433714.5	TSL:1	n.555C>T		non_coding_transcript_exon	Exon 6 of 24	ENSP00000412159.1	F8WCG5

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1224 AN: 152078 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00221 AC: 556 AN: 251240 AF XY: 0.00161

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000790 AC: 1155 AN: 1461706 Hom.: 14 Cov.: 31 AF XY: 0.000664 AC XY: 483 AN XY: 727160

African (AFR) AF: 0.0281 AC: 939 AN: 33472

American (AMR) AF: 0.00190 AC: 85 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111884

Other (OTH) AF: 0.00161 AC: 97 AN: 60390

GnomAD4 genome AF: 0.00810 AC: 1233 AN: 152196 Hom.: 20 Cov.: 32 AF XY: 0.00794 AC XY: 591 AN XY: 74406

African (AFR) AF: 0.0284 AC: 1178 AN: 41524

American (AMR) AF: 0.00249 AC: 38 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68014

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

Alfa AF: 0.00396 Hom.: 2

Bravo AF: 0.00928

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Bardet-Biedl syndrome 9 (2)
-	-	1	Bardet-Biedl syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	3.5
DANN	Benign	0.66
PhyloP100		-0.12
Mutation Taster		=99/1	polymorphism

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: rs35440033; hg19: chr7-33296960;