chr5-90690065-A-G

Variant names:

• chr5-90690065-A-G
• rs10037067
• NM_032119.4:c.6695A>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.6695A>G​(p.Tyr2232Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,545,226 control chromosomes in the GnomAD database, including 94,105 homozygotes. In-silico tool predicts 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. Y2232R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.34 (9004 hom., cov: 31)
  • Exomes 𝑓: 0.34 (85101 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.16
• Publications: 42 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=5.3060055E-4).
• BP6: Variant 5-90690065-A-G is Benign according to our data. Variant chr5-90690065-A-G is described in ClinVar as Benign. ClinVar VariationId is 46356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.473 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.6695A>G	p.Tyr2232Cys	missense	Exon 30 of 90	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.6794A>G		non_coding_transcript_exon	Exon 30 of 90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.6695A>G	p.Tyr2232Cys	missense	Exon 30 of 90	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000640403.1	TSL:5	c.3986A>G	p.Tyr1329Cys	missense	Exon 20 of 29	ENSP00000492531.1	A0A1W2PRC7
	ADGRV1	ENST00000639473.1	TSL:5	n.2154A>G		non_coding_transcript_exon	Exon 10 of 23

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51372 AN: 151848 Hom.: 8980 Cov.: 31

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.386

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.365 AC: 66647 AN: 182748 AF XY: 0.356

Gnomad AFR exome AF: 0.291

Gnomad AMR exome AF: 0.574

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.365

Gnomad FIN exome AF: 0.333

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.345 AC: 480345 AN: 1393260 Hom.: 85101 Cov.: 26 AF XY: 0.343 AC XY: 236610 AN XY: 690630

African (AFR) AF: 0.281 AC: 9029 AN: 32154

American (AMR) AF: 0.560 AC: 20915 AN: 37318

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 6911 AN: 25214

East Asian (EAS) AF: 0.433 AC: 16357 AN: 37784

South Asian (SAS) AF: 0.327 AC: 26296 AN: 80452

European-Finnish (FIN) AF: 0.339 AC: 17243 AN: 50838

Middle Eastern (MID) AF: 0.280 AC: 1586 AN: 5674

European-Non Finnish (NFE) AF: 0.340 AC: 362333 AN: 1065844

Other (OTH) AF: 0.339 AC: 19675 AN: 57982

GnomAD4 genome AF: 0.338 AC: 51426 AN: 151966 Hom.: 9004 Cov.: 31 AF XY: 0.341 AC XY: 25321 AN XY: 74284

African (AFR) AF: 0.293 AC: 12155 AN: 41450

American (AMR) AF: 0.482 AC: 7355 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 968 AN: 3472

East Asian (EAS) AF: 0.386 AC: 1992 AN: 5162

South Asian (SAS) AF: 0.322 AC: 1551 AN: 4816

European-Finnish (FIN) AF: 0.334 AC: 3525 AN: 10564

Middle Eastern (MID) AF: 0.288 AC: 84 AN: 292

European-Non Finnish (NFE) AF: 0.334 AC: 22706 AN: 67928

Other (OTH) AF: 0.364 AC: 767 AN: 2108

Alfa AF: 0.341 Hom.: 35598

Bravo AF: 0.353

TwinsUK AF: 0.333 AC: 1233

ALSPAC AF: 0.351 AC: 1351

ESP6500AA AF: 0.293 AC: 1070

ESP6500EA AF: 0.329 AC: 2688

ExAC AF: 0.309 AC: 35600

Asia WGS AF: 0.351 AC: 1221 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C (1)
-	-	1	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.00053	T
MetaSVM	Benign	-0.91	T
PhyloP100		2.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.17
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.24
MPC		0.33
ClinPred		0.027	T
GERP RS		2.8
Varity_R		0.38
gMVP		0.73
Mutation Taster		=90/10	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: rs10037067; hg19: chr5-89985882; COSMIC: COSV67985306; COSMIC: COSV67985306;