5-90694332-A-G

Variant names:

• chr5-90694332-A-G
• rs75191159
• NM_032119.4:c.7576A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032119.4(ADGRV1):​c.7576A>G​(p.Ile2526Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,613,950 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2526L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (91 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (84 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.257
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015960932).
• BP6: Variant 5-90694332-A-G is Benign according to our data. Variant chr5-90694332-A-G is described in ClinVar as Benign. ClinVar VariationId is 46376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0669 is higher than 0.05.

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.7576A>G	p.Ile2526Val	missense	Exon 33 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.7592A>G		non_coding_transcript_exon	Exon 33 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.7576A>G	p.Ile2526Val	missense	Exon 33 of 90	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000509621.1	TSL:1	n.273A>G		non_coding_transcript_exon	Exon 1 of 26
	ADGRV1	ENST00000640403.1	TSL:5	c.4867A>G	p.Ile1623Val	missense	Exon 23 of 29	ENSP00000492531.1	A0A1W2PRC7

Frequencies

GnomAD3 genomes AF: 0.0198 AC: 3008 AN: 152186 Hom.: 92 Cov.: 33

Gnomad AFR AF: 0.0691

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00477 AC: 1188 AN: 249050 AF XY: 0.00377

Gnomad AFR exome AF: 0.0679

Gnomad AMR exome AF: 0.00290

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00198 AC: 2899 AN: 1461646 Hom.: 84 Cov.: 37 AF XY: 0.00172 AC XY: 1247 AN XY: 727098

African (AFR) AF: 0.0665 AC: 2226 AN: 33472

American (AMR) AF: 0.00349 AC: 156 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.000218 AC: 242 AN: 1111848

Other (OTH) AF: 0.00416 AC: 251 AN: 60372

GnomAD4 genome AF: 0.0198 AC: 3013 AN: 152304 Hom.: 91 Cov.: 33 AF XY: 0.0188 AC XY: 1398 AN XY: 74478

African (AFR) AF: 0.0690 AC: 2868 AN: 41564

American (AMR) AF: 0.00674 AC: 103 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68028

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00659 Hom.: 45

Bravo AF: 0.0220

ESP6500AA AF: 0.0656 AC: 254

ESP6500EA AF: 0.000241 AC: 2

ExAC AF: 0.00573 AC: 693

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.034
DANN	Benign	0.85
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.26
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.060
Sift	Benign	0.28	T
Sift4G	Benign	0.10	T
Polyphen		0.0020	B
Vest4		0.083
MVP		0.21
MPC		0.051
ClinPred		0.0031	T
GERP RS		-3.0
Varity_R		0.028
gMVP		0.49
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs75191159; hg19: chr5-89990149;