rs2366777

Variant names:

• chr5-90647754-G-T
• rs2366777
• NM_032119.4:c.3279G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-90647754-G-T
• chr5-90647754-G-A

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.3279G>T​(p.Leu1093Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 1,609,430 control chromosomes in the GnomAD database, including 366,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1093L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.74 (42871 hom., cov: 32)
  • Exomes 𝑓: 0.66 (323625 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.293
• Publications: 40 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=8.170927E-7).
• BP6: Variant 5-90647754-G-T is Benign according to our data. Variant chr5-90647754-G-T is described in ClinVar as Benign. ClinVar VariationId is 46313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.903 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.3279G>T	p.Leu1093Phe	missense	Exon 17 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.3378G>T		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.3279G>T	p.Leu1093Phe	missense	Exon 17 of 90	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000640403.1	TSL:5	c.582G>T	p.Leu194Phe	missense	Exon 7 of 29	ENSP00000492531.1	A0A1W2PRC7
	ADGRV1	ENST00000504142.2	TSL:5	n.2045G>T		non_coding_transcript_exon	Exon 11 of 14

Frequencies

GnomAD3 genomes AF: 0.741 AC: 112562 AN: 151944 Hom.: 42800 Cov.: 32

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.748

GnomAD2 exomes AF: 0.711 AC: 176353 AN: 247886 AF XY: 0.702

Gnomad AFR exome AF: 0.915

Gnomad AMR exome AF: 0.827

Gnomad ASJ exome AF: 0.669

Gnomad EAS exome AF: 0.801

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.704

GnomAD4 exome AF: 0.663 AC: 966248 AN: 1457368 Hom.: 323625 Cov.: 37 AF XY: 0.663 AC XY: 480374 AN XY: 724988

African (AFR) AF: 0.916 AC: 30555 AN: 33356

American (AMR) AF: 0.823 AC: 36712 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 17479 AN: 26084

East Asian (EAS) AF: 0.817 AC: 32402 AN: 39672

South Asian (SAS) AF: 0.719 AC: 61847 AN: 86032

European-Finnish (FIN) AF: 0.668 AC: 35478 AN: 53140

Middle Eastern (MID) AF: 0.698 AC: 4015 AN: 5756

European-Non Finnish (NFE) AF: 0.637 AC: 706228 AN: 1108518

Other (OTH) AF: 0.690 AC: 41532 AN: 60200

GnomAD4 genome AF: 0.741 AC: 112688 AN: 152062 Hom.: 42871 Cov.: 32 AF XY: 0.744 AC XY: 55255 AN XY: 74314

African (AFR) AF: 0.911 AC: 37802 AN: 41514

American (AMR) AF: 0.780 AC: 11920 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2326 AN: 3466

East Asian (EAS) AF: 0.813 AC: 4200 AN: 5166

South Asian (SAS) AF: 0.725 AC: 3492 AN: 4818

European-Finnish (FIN) AF: 0.662 AC: 6981 AN: 10540

Middle Eastern (MID) AF: 0.687 AC: 202 AN: 294

European-Non Finnish (NFE) AF: 0.640 AC: 43524 AN: 67966

Other (OTH) AF: 0.752 AC: 1588 AN: 2112

Alfa AF: 0.676 Hom.: 154673

Bravo AF: 0.761

TwinsUK AF: 0.629 AC: 2332

ALSPAC AF: 0.649 AC: 2502

ESP6500AA AF: 0.912 AC: 3338

ESP6500EA AF: 0.645 AC: 5258

ExAC AF: 0.709 AC: 85636

Asia WGS AF: 0.808 AC: 2809 AN: 3478

EpiCase AF: 0.652

EpiControl AF: 0.651

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	2	Usher syndrome type 2C (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.035
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.29
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.29
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.061
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.52		Gain of catalytic residue at L1093 (P = 0.2302)
MPC		0.050
ClinPred		0.00040	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.29
Mutation Taster		=95/5	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: rs2366777; hg19: chr5-89943571; COSMIC: COSV108245831;