rs138072724

Variant names:

• chr7-33344585-C-T
• rs138072724
• NM_198428.3:c.1280C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_198428.3(BBS9):​c.1280C>T​(p.Ala427Val) variant causes a missense change. The variant allele was found at a frequency of 0.00724 in 1,613,792 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A427S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (61 hom.)
• Consequence: BBS9 NM_198428.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 6.05
• Publications: 14 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: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074636936).
• BP6: Variant 7-33344585-C-T is Benign according to our data. Variant chr7-33344585-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194138.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00574 (874/152244) while in subpopulation NFE AF = 0.00909 (618/68004). AF 95% confidence interval is 0.00849. There are 6 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	NM_198428.3	MANE Select	c.1280C>T	p.Ala427Val	missense	Exon 12 of 23	NP_940820.1
	BBS9	NM_001348041.4		c.1280C>T	p.Ala427Val	missense	Exon 12 of 23	NP_001334970.1
	BBS9	NM_001348036.1		c.1280C>T	p.Ala427Val	missense	Exon 12 of 23	NP_001334965.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBS9	ENST00000242067.11	TSL:1 MANE Select	c.1280C>T	p.Ala427Val	missense	Exon 12 of 23	ENSP00000242067.6
	BBS9	ENST00000433714.5	TSL:1	n.1280C>T		non_coding_transcript_exon	Exon 12 of 24	ENSP00000412159.1
	BBS9	ENST00000671871.1		c.1403C>T	p.Ala468Val	missense	Exon 13 of 24	ENSP00000499908.1

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 874 AN: 152126 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00909

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00493 AC: 1241 AN: 251488 AF XY: 0.00497

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00755

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00740 AC: 10817 AN: 1461548 Hom.: 61 Cov.: 31 AF XY: 0.00736 AC XY: 5349 AN XY: 727088

African (AFR) AF: 0.00111 AC: 37 AN: 33478

American (AMR) AF: 0.00134 AC: 60 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000651 AC: 17 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86254

European-Finnish (FIN) AF: 0.0111 AC: 593 AN: 53408

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00874 AC: 9714 AN: 1111740

Other (OTH) AF: 0.00542 AC: 327 AN: 60376

GnomAD4 genome AF: 0.00574 AC: 874 AN: 152244 Hom.: 6 Cov.: 31 AF XY: 0.00584 AC XY: 435 AN XY: 74434

African (AFR) AF: 0.00149 AC: 62 AN: 41550

American (AMR) AF: 0.00177 AC: 27 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.0152 AC: 161 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00909 AC: 618 AN: 68004

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00709 Hom.: 23

Bravo AF: 0.00398

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00463 AC: 562

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00557

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.28
Sift	Benign	0.27	T
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.50
MVP		0.76
MPC		0.079
ClinPred		0.032	T
GERP RS		4.9
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.34
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs138072724; hg19: chr7-33384197; COSMIC: COSV54166336; COSMIC: COSV54166336;