rs200528472

Variant names:

• chr5-90725621-A-G
• rs200528472
• NM_032119.4:c.10126A>G

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.10126A>G​(p.Ile3376Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,582,018 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0730
• Publications: 0 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

LOC105379077 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004339963).
• BP6: Variant 5-90725621-A-G is Benign according to our data. Variant chr5-90725621-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197599.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 = 0.00171 (261/152296) while in subpopulation AFR AF = 0.00601 (250/41572). AF 95% confidence interval is 0.0054. There are 0 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.10126A>G	p.Ile3376Val	missense	Exon 48 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.10142A>G		non_coding_transcript_exon	Exon 48 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.10126A>G	p.Ile3376Val	missense	Exon 48 of 90	ENSP00000384582.2
	ADGRV1	ENST00000509621.1	TSL:1	n.2823A>G		non_coding_transcript_exon	Exon 16 of 26
	ADGRV1	ENST00000640374.1	TSL:5	n.3270A>G		non_coding_transcript_exon	Exon 18 of 27

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00601

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000457 AC: 112 AN: 244854 AF XY: 0.000332

Gnomad AFR exome AF: 0.00606

Gnomad AMR exome AF: 0.000447

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000178 AC: 255 AN: 1429722 Hom.: 2 Cov.: 26 AF XY: 0.000159 AC XY: 113 AN XY: 712930

African (AFR) AF: 0.00602 AC: 197 AN: 32742

American (AMR) AF: 0.000386 AC: 17 AN: 44030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39368

South Asian (SAS) AF: 0.0000474 AC: 4 AN: 84342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.000531 AC: 3 AN: 5650

European-Non Finnish (NFE) AF: 0.00000184 AC: 2 AN: 1085128

Other (OTH) AF: 0.000540 AC: 32 AN: 59244

GnomAD4 genome AF: 0.00171 AC: 261 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00166 AC XY: 124 AN XY: 74476

African (AFR) AF: 0.00601 AC: 250 AN: 41572

American (AMR) AF: 0.000392 AC: 6 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000700 Hom.: 1

Bravo AF: 0.00191

ESP6500AA AF: 0.00663 AC: 24

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000489 AC: 59

Asia WGS AF: 0.000289 AC: 1 AN: 3468

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	ADGRV1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.32
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.073
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.014
Sift	Benign	0.65	T
Sift4G	Benign	0.72	T
Polyphen		0.0	B
Vest4		0.051
MVP		0.16
MPC		0.042
ClinPred		0.00087	T
GERP RS		-0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.20
Mutation Taster		=98/2	polymorphism

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: rs200528472; hg19: chr5-90021438;