rs576743510

Positions:

• chr5-90763332-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_032119.4(ADGRV1):​c.12148G>A​(p.Asp4050Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,593,016 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. D4050D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.08

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.016032457).
• BP6: Variant 5-90763332-G-A is Benign according to our data. Variant chr5-90763332-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 504943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.12148G>A	p.Asp4050Asn	missense_variant	59/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.12148G>A	p.Asp4050Asn	missense_variant	59/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000332 AC: 5 AN: 150690 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000374 AC: 92 AN: 246200 Hom.: 0 AF XY: 0.000262 AC XY: 35 AN XY: 133516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000984

Gnomad OTH exome AF: 0.000334

GnomAD4 exome AF: 0.000138 AC: 199 AN: 1442218 Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 73 AN XY: 714390

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000280

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000874

Gnomad4 OTH exome AF: 0.000168

GnomAD4 genome AF: 0.0000332 AC: 5 AN: 150798 Hom.: 0 Cov.: 32 AF XY: 0.0000544 AC XY: 4 AN XY: 73552

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000692 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000397 AC: 48

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2023	See Variant Classification Assertion Criteria. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 11, 2016

p.Asp4050Asn in exon 50 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.4% (43/10654) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs576743510). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
Polyphen		0.81	P;P;.
Vest4		0.34
MutPred		0.34		Loss of stability (P = 0.0148);Loss of stability (P = 0.0148);.;
MVP		0.53
MPC		0.099
ClinPred		0.078	T
GERP RS		5.3
Varity_R		0.17
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs576743510; hg19: chr5-90059149; COSMIC: COSV67994519; COSMIC: COSV67994519;