rs61764067

Variant names:

• chr7-33340944-G-A
• rs61764067
• NM_198428.3:c.1246G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-33340944-G-A
• chr7-33340944-G-C
• chr7-33340944-G-T

Variant summary

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

The NM_001348041.4(BBS9):​c.1246G>A​(p.Val416Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,613,512 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (34 hom.)
• Consequence: BBS9 NM_001348041.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.25
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039181113).
• BP6: Variant 7-33340944-G-A is Benign according to our data. Variant chr7-33340944-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00389 (592/152152) while in subpopulation EAS AF = 0.0155 (80/5174). AF 95% confidence interval is 0.0127. There are 4 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348041.4. 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.1246G>A	p.Val416Met	missense	Exon 11 of 23	NP_940820.1
	BBS9	NM_001348041.4		c.1246G>A	p.Val416Met	missense	Exon 11 of 23	NP_001334970.1
	BBS9	NM_001348036.1		c.1246G>A	p.Val416Met	missense	Exon 11 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.1246G>A	p.Val416Met	missense	Exon 11 of 23	ENSP00000242067.6
	BBS9	ENST00000433714.5	TSL:1	n.1246G>A		non_coding_transcript_exon	Exon 11 of 24	ENSP00000412159.1
	BBS9	ENST00000942912.1		c.1372G>A	p.Val458Met	missense	Exon 12 of 24	ENSP00000612971.1

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 152034 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00957

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00746

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00607 AC: 1526 AN: 251382 AF XY: 0.00551

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.0132

Gnomad FIN exome AF: 0.00619

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00401 AC: 5866 AN: 1461360 Hom.: 34 Cov.: 30 AF XY: 0.00395 AC XY: 2869 AN XY: 726968

African (AFR) AF: 0.000627 AC: 21 AN: 33472

American (AMR) AF: 0.0180 AC: 803 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00961 AC: 251 AN: 26124

East Asian (EAS) AF: 0.0244 AC: 968 AN: 39666

South Asian (SAS) AF: 0.00155 AC: 134 AN: 86242

European-Finnish (FIN) AF: 0.00669 AC: 357 AN: 53358

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00276 AC: 3063 AN: 1111634

Other (OTH) AF: 0.00439 AC: 265 AN: 60374

GnomAD4 genome AF: 0.00389 AC: 592 AN: 152152 Hom.: 4 Cov.: 32 AF XY: 0.00397 AC XY: 295 AN XY: 74398

African (AFR) AF: 0.000674 AC: 28 AN: 41524

American (AMR) AF: 0.00955 AC: 146 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.0155 AC: 80 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00746 AC: 79 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 67980

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00359 Hom.: 5

Bravo AF: 0.00413

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00556 AC: 675

Asia WGS AF: 0.00808 AC: 29 AN: 3478

EpiCase AF: 0.00289

EpiControl AF: 0.00219

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.011
DANN	Benign	0.77
DEOGEN2	Benign	0.056	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.69	N
PhyloP100		-2.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.15
Sift	Benign	0.26	T
Sift4G	Benign	0.25	T
Polyphen		0.0070	B
Vest4		0.11
MVP		0.43
MPC		0.064
ClinPred		0.0070	T
GERP RS		-9.0
Varity_R		0.058
gMVP		0.12
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs61764067; hg19: chr7-33380556; COSMIC: COSV54169251; COSMIC: COSV54169251;