rs148097083

Variant names:

• chr5-90647764-G-A
• rs148097083
• NM_032119.4:c.3289G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-90647764-G-A
• chr5-90647764-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_032119.4(ADGRV1):​c.3289G>A​(p.Gly1097Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,609,230 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G1097G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (33 hom.)
• Consequence: ADGRV1 NM_032119.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 9.64
• Publications: 8 publications found

Genes affected

ADGRV1 (HGNC:17416): (adhesion G protein-coupled receptor V1) This gene encodes a member of the G-protein coupled receptor superfamily. The encoded protein contains a 7-transmembrane receptor domain, binds calcium and is expressed in the central nervous system. Mutations in this gene are associated with Usher syndrome 2 and familial febrile seizures. Several alternatively spliced transcripts have been described. [provided by RefSeq, Jul 2008]

ADGRV1 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• febrile seizures, familial, 4

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 5-90647764-G-A is Benign according to our data. Variant chr5-90647764-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00292 (4260/1456984) while in subpopulation MID AF = 0.00661 (38/5748). AF 95% confidence interval is 0.00495. There are 33 homozygotes in GnomAdExome4. There are 2141 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032119.4. 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
	ADGRV1	NM_032119.4	MANE Select	c.3289G>A	p.Gly1097Ser	missense splice_region	Exon 17 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.3388G>A		splice_region non_coding_transcript_exon	Exon 17 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.3289G>A	p.Gly1097Ser	missense splice_region	Exon 17 of 90	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000640403.1	TSL:5	c.592G>A	p.Gly198Ser	missense splice_region	Exon 7 of 29	ENSP00000492531.1	A0A1W2PRC7
	ADGRV1	ENST00000504142.2	TSL:5	n.2055G>A		splice_region non_coding_transcript_exon	Exon 11 of 14

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 717 AN: 152128 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0344

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00521 AC: 1284 AN: 246676 AF XY: 0.00515

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.00140

Gnomad ASJ exome AF: 0.00943

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.0341

Gnomad NFE exome AF: 0.00325

Gnomad OTH exome AF: 0.00569

GnomAD4 exome AF: 0.00292 AC: 4260 AN: 1456984 Hom.: 33 Cov.: 32 AF XY: 0.00296 AC XY: 2141 AN XY: 724414

African (AFR) AF: 0.000150 AC: 5 AN: 33230

American (AMR) AF: 0.00180 AC: 80 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.00930 AC: 242 AN: 26034

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39646

South Asian (SAS) AF: 0.000687 AC: 59 AN: 85896

European-Finnish (FIN) AF: 0.0295 AC: 1556 AN: 52712

Middle Eastern (MID) AF: 0.00661 AC: 38 AN: 5748

European-Non Finnish (NFE) AF: 0.00189 AC: 2092 AN: 1109106

Other (OTH) AF: 0.00311 AC: 187 AN: 60208

GnomAD4 genome AF: 0.00471 AC: 717 AN: 152246 Hom.: 8 Cov.: 32 AF XY: 0.00625 AC XY: 465 AN XY: 74424

African (AFR) AF: 0.000481 AC: 20 AN: 41544

American (AMR) AF: 0.00222 AC: 34 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.0344 AC: 365 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00344 AC: 234 AN: 68016

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00258 Hom.: 2

Bravo AF: 0.00210

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000273 AC: 1

ESP6500EA AF: 0.00343 AC: 28

ExAC AF: 0.00442 AC: 534

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00279

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.30	T
PhyloP100		9.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.75
MVP		0.74
MPC		0.30
ClinPred		0.045	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.49
gMVP		0.70
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
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: rs148097083; hg19: chr5-89943581; COSMIC: COSV105343951;