rs2247870

Variant names:

• chr5-90855772-G-A
• rs2247870
• NM_032119.4:c.17626G>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.17626G>A​(p.Val5876Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 1,589,340 control chromosomes in the GnomAD database, including 232,939 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (18112 hom., cov: 32)
  • Exomes 𝑓: 0.54 (214827 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.35
• Publications: 58 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=2.5032716E-6).
• BP6: Variant 5-90855772-G-A is Benign according to our data. Variant chr5-90855772-G-A is described in ClinVar as Benign. ClinVar VariationId is 46291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.629 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.17626G>A	p.Val5876Ile	missense	Exon 82 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.17642G>A		non_coding_transcript_exon	Exon 82 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.17626G>A	p.Val5876Ile	missense	Exon 82 of 90	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000638510.1	TSL:1	n.4893G>A		non_coding_transcript_exon	Exon 18 of 26
	ADGRV1	ENST00000425867.3	TSL:5	c.6580G>A	p.Val2194Ile	missense	Exon 30 of 38	ENSP00000392618.3	A0A1X7SBU6

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69763 AN: 151882 Hom.: 18098 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.489

Gnomad AMR AF: 0.639

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.510

GnomAD2 exomes AF: 0.544 AC: 126932 AN: 233486 AF XY: 0.542

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.727

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.539

Gnomad FIN exome AF: 0.565

Gnomad NFE exome AF: 0.546

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.542 AC: 779132 AN: 1437338 Hom.: 214827 Cov.: 30 AF XY: 0.541 AC XY: 385841 AN XY: 713248

African (AFR) AF: 0.184 AC: 5999 AN: 32578

American (AMR) AF: 0.714 AC: 29167 AN: 40856

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 11958 AN: 25322

East Asian (EAS) AF: 0.575 AC: 22492 AN: 39144

South Asian (SAS) AF: 0.534 AC: 43234 AN: 80964

European-Finnish (FIN) AF: 0.566 AC: 30072 AN: 53130

Middle Eastern (MID) AF: 0.493 AC: 2803 AN: 5680

European-Non Finnish (NFE) AF: 0.548 AC: 602344 AN: 1100152

Other (OTH) AF: 0.522 AC: 31063 AN: 59512

GnomAD4 genome AF: 0.459 AC: 69786 AN: 152002 Hom.: 18112 Cov.: 32 AF XY: 0.464 AC XY: 34462 AN XY: 74300

African (AFR) AF: 0.198 AC: 8229 AN: 41488

American (AMR) AF: 0.640 AC: 9752 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1627 AN: 3470

East Asian (EAS) AF: 0.561 AC: 2891 AN: 5154

South Asian (SAS) AF: 0.521 AC: 2512 AN: 4820

European-Finnish (FIN) AF: 0.565 AC: 5969 AN: 10564

Middle Eastern (MID) AF: 0.507 AC: 149 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37127 AN: 67950

Other (OTH) AF: 0.515 AC: 1087 AN: 2112

Alfa AF: 0.520 Hom.: 70864

Bravo AF: 0.451

TwinsUK AF: 0.538 AC: 1996

ALSPAC AF: 0.550 AC: 2121

ESP6500AA AF: 0.195 AC: 759

ESP6500EA AF: 0.547 AC: 4531

ExAC AF: 0.536 AC: 64763

Asia WGS AF: 0.563 AC: 1958 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Usher syndrome type 2C (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-0.92	T
PhyloP100		3.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.094
Sift	Benign	0.24	T
Sift4G	Benign	0.19	T
Polyphen		0.58	P
Vest4		0.12
MPC		0.042
ClinPred		0.0084	T
GERP RS		4.6
Varity_R		0.039
gMVP		0.20
Mutation Taster		=92/8	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: rs2247870; hg19: chr5-90151589; COSMIC: COSV67978849; COSMIC: COSV67978849;