7-33146286-A-G

Variant names:

• chr7-33146286-A-G
• rs4498440
• NM_198428.3:c.34A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001348038.3(BBS9):​c.-244A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,614,020 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (36 hom.)
• Consequence: BBS9 NM_001348038.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.46
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032102764).
• BP6: Variant 7-33146286-A-G is Benign according to our data. Variant chr7-33146286-A-G is described in ClinVar as Benign. ClinVar VariationId is 263130.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 = 0.0128 (1954/152310) while in subpopulation AFR AF = 0.0448 (1861/41550). AF 95% confidence interval is 0.0431. There are 49 homozygotes in GnomAd4. There are 923 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

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.34A>G	p.Thr12Ala	missense	Exon 2 of 23	NP_940820.1	Q3SYG4-1
	BBS9	NM_001348038.3		c.-244A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 23	NP_001334967.1
	BBS9	NM_001348039.3		c.-244A>G		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.34A>G	p.Thr12Ala	missense	Exon 2 of 23	ENSP00000242067.6	Q3SYG4-1
	BBS9	ENST00000433714.5	TSL:1	n.34A>G		non_coding_transcript_exon	Exon 2 of 24	ENSP00000412159.1	F8WCG5
	BBS9	ENST00000673431.1		c.-102A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	ENSP00000500552.1	A0A5F9ZHP5

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1939 AN: 152192 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00334 AC: 839 AN: 251472 AF XY: 0.00255

Gnomad AFR exome AF: 0.0447

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00138 AC: 2017 AN: 1461710 Hom.: 36 Cov.: 30 AF XY: 0.00122 AC XY: 885 AN XY: 727178

African (AFR) AF: 0.0480 AC: 1608 AN: 33470

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000939 AC: 81 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111868

Other (OTH) AF: 0.00321 AC: 194 AN: 60390

GnomAD4 genome AF: 0.0128 AC: 1954 AN: 152310 Hom.: 49 Cov.: 32 AF XY: 0.0124 AC XY: 923 AN XY: 74494

African (AFR) AF: 0.0448 AC: 1861 AN: 41550

American (AMR) AF: 0.00405 AC: 62 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68028

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00337 Hom.: 27

Bravo AF: 0.0144

ESP6500AA AF: 0.0402 AC: 177

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00413 AC: 501

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.52	N
PhyloP100		2.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.28	T
Sift4G	Benign	0.42	T
Polyphen		0.014	B
Vest4		0.11
MVP		0.72
MPC		0.080
ClinPred		0.013	T
GERP RS		2.8
PromoterAI		0.041	Neutral
Varity_R		0.27
gMVP		0.41
Mutation Taster		=294/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs4498440; hg19: chr7-33185898;