rs138072724

chr7-33344585-C-T

Variant summary

Our verdict is Benign. Variant got -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). Synonymous variant affecting the same amino acid position (i.e. A427A) has been classified as Likely benign.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 194138.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=4, Uncertain_significance=1}. Variant chr7-33344585-C-T is described in Lovd as [Likely_pathogenic]. Variant chr7-33344585-C-T is described in Lovd as [Likely_benign]. Variant chr7-33344585-C-T is described in Lovd as [Benign]. Variant chr7-33344585-C-T is described in Lovd as [Pathogenic].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BBS9	NM_198428.3	c.1280C>T	p.Ala427Val	missense_variant	12/23	ENST00000242067.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BBS9	ENST00000242067.11	c.1280C>T	p.Ala427Val	missense_variant	12/23	1	NM_198428.3	P3

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

GnomAD3 exomes AF: 0.00493 AC: 1241 AN: 251488 Hom.: 4 AF XY: 0.00497 AC XY: 675 AN XY: 135916

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 SAS exome AF: 0.000719

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

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.00874

Gnomad4 OTH exome AF: 0.00542

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

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0152

Gnomad4 NFE AF: 0.00909

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00739 Hom.: 12

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	BBS9: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 2016	The A427V variant in the BBS9 gene has been published previously as a rare sequence variant with a frequency of0.9% (Lim et al., 2014); this variant was identified in the homozygous state in 1/9033 control individuals. TheNHLBI Exome Sequencing Project reports A427V was observed in 0.79% (68/8600) alleles from individuals ofEuropean American ancestry, and was present in the homozygous state in one individual. The A427V variant is aconservative amino acid substitution, which is not likely to impact secondary protein structure as these residues sharesimilar properties. This substitution occurs at a position where amino acids with similar properties to Alanine aretolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant isdamaging to the protein structure/function. We interpret A427V as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 22, 2017	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 21, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Bardet-Biedl syndrome 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Bardet-Biedl syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;D
MetaRNN	Benign	0.0075	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.27	T;T;T;T
Sift4G	Benign	0.24	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.50
MVP		0.76
MPC		0.079
ClinPred		0.032	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs138072724; hg19: chr7-33384197; COSMIC: COSV54166336; COSMIC: COSV54166336;