rs111033470

Variant names:

• chr5-90692732-G-A
• rs111033470
• NM_032119.4:c.7079G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-90692732-G-A
• chr5-90692732-G-C

Variant summary

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

The NM_032119.4(ADGRV1):​c.7079G>A​(p.Arg2360His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,608,016 control chromosomes in the GnomAD database, including 23 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2360C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (8 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.35
• 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: ClinGen, Orphanet
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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=0.006472975).
• BP6: Variant 5-90692732-G-A is Benign according to our data. Variant chr5-90692732-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00724 (1101/152170) while in subpopulation AFR AF = 0.0255 (1059/41506). AF 95% confidence interval is 0.0242. There are 15 homozygotes in GnomAd4. There are 513 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.7079G>A	p.Arg2360His	missense	Exon 32 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.7095G>A		non_coding_transcript_exon	Exon 32 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.7079G>A	p.Arg2360His	missense	Exon 32 of 90	ENSP00000384582.2
	ADGRV1	ENST00000640403.1	TSL:5	c.4370G>A	p.Arg1457His	missense	Exon 22 of 29	ENSP00000492531.1
	ADGRV1	ENST00000639473.1	TSL:5	n.2538G>A		non_coding_transcript_exon	Exon 12 of 23

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1096 AN: 152052 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00188 AC: 450 AN: 239870 AF XY: 0.00147

Gnomad AFR exome AF: 0.0277

Gnomad AMR exome AF: 0.000794

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.0000644

Gnomad OTH exome AF: 0.000516

GnomAD4 exome AF: 0.000723 AC: 1052 AN: 1455846 Hom.: 8 Cov.: 31 AF XY: 0.000655 AC XY: 474 AN XY: 723596

African (AFR) AF: 0.0259 AC: 864 AN: 33342

American (AMR) AF: 0.000891 AC: 39 AN: 43758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25974

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.0000471 AC: 4 AN: 84890

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53214

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.0000361 AC: 40 AN: 1109220

Other (OTH) AF: 0.00168 AC: 101 AN: 60156

GnomAD4 genome AF: 0.00724 AC: 1101 AN: 152170 Hom.: 15 Cov.: 32 AF XY: 0.00690 AC XY: 513 AN XY: 74390

African (AFR) AF: 0.0255 AC: 1059 AN: 41506

American (AMR) AF: 0.00190 AC: 29 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00271 Hom.: 8

Bravo AF: 0.00818

ESP6500AA AF: 0.0282 AC: 106

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00240 AC: 290

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C (1)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.043
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.080
Sift	Benign	0.052	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.15	B
Vest4		0.19
MVP		0.55
MPC		0.34
ClinPred		0.035	T
GERP RS		4.2
Varity_R		0.084
gMVP		0.60
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs111033470; hg19: chr5-89988549; COSMIC: COSV67983767; COSMIC: COSV67983767;