NM_032119.4:c.1718G>T

Variant names:

• chr5-90629418-G-T
• rs200789563
• NM_032119.4:c.1718G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032119.4(ADGRV1):​c.1718G>T​(p.Gly573Val) variant causes a missense change. The variant allele was found at a frequency of 0.000233 in 1,613,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G573S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:9 B:1
• Conservation: PhyloP100: 5.10
• Publications: 7 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15449491).

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.1718G>T	p.Gly573Val	missense	Exon 9 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.1817G>T		non_coding_transcript_exon	Exon 9 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.1718G>T	p.Gly573Val	missense	Exon 9 of 90	ENSP00000384582.2
	ADGRV1	ENST00000504142.2	TSL:5	n.484G>T		non_coding_transcript_exon	Exon 3 of 14
	ADGRV1	ENST00000640109.1	TSL:5	n.1814G>T		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 151794 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000297 AC: 74 AN: 249058 AF XY: 0.000289

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000220 AC: 321 AN: 1461588 Hom.: 0 Cov.: 31 AF XY: 0.000216 AC XY: 157 AN XY: 727068

African (AFR) AF: 0.000478 AC: 16 AN: 33480

American (AMR) AF: 0.00136 AC: 61 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000203 AC: 226 AN: 1111804

Other (OTH) AF: 0.000265 AC: 16 AN: 60368

GnomAD4 genome AF: 0.000362 AC: 55 AN: 151912 Hom.: 0 Cov.: 31 AF XY: 0.000364 AC XY: 27 AN XY: 74210

African (AFR) AF: 0.000555 AC: 23 AN: 41456

American (AMR) AF: 0.00144 AC: 22 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

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

European-Finnish (FIN) AF: 0.0000951 AC: 1 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000213 Hom.: 1

Bravo AF: 0.000499

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000536 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000182 AC: 22

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	2	-	not specified (2)
-	1	-	ADGRV1-related disorder (1)
-	1	-	Febrile seizures, familial, 4 (1)
1	-	-	Idiopathic generalized epilepsy (1)
1	-	-	Usher syndrome type 2 (1)
-	1	-	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.33	T
PhyloP100		5.1
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.76
MVP		0.67
MPC		0.34
ClinPred		0.087	T
GERP RS		4.6
Varity_R		0.59
gMVP		0.80
Mutation Taster		=58/42	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: rs200789563; hg19: chr5-89925235;