rs201236317

Positions:

• chr5-90627571-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_032119.4(ADGRV1):​c.1033C>A​(p.Gln345Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000625 in 1,613,694 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q345Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (2 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.12

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01561898).
• BP6: Variant 5-90627571-C-A is Benign according to our data. Variant chr5-90627571-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227388.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}. Variant chr5-90627571-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.1033C>A	p.Gln345Lys	missense_variant	7/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.1033C>A	p.Gln345Lys	missense_variant	7/90	1	NM_032119.4	P1
ADGRV1	ENST00000640281.1	n.1092C>A		non_coding_transcript_exon_variant	7/7	1
ADGRV1	ENST00000640083.1	n.738C>A		non_coding_transcript_exon_variant	5/6	5
ADGRV1	ENST00000640109.1	n.1129C>A		non_coding_transcript_exon_variant	7/9	5

Frequencies

GnomAD3 genomes AF: 0.000717 AC: 109 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000855 AC: 213 AN: 249052 Hom.: 0 AF XY: 0.000792 AC XY: 107 AN XY: 135100

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000615 AC: 899 AN: 1461580 Hom.: 2 Cov.: 32 AF XY: 0.000620 AC XY: 451 AN XY: 727076

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.000672

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.000717 AC: 109 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.000929 AC XY: 69 AN XY: 74292

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.000911

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000828 Hom.: 1

Bravo AF: 0.000495

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000975 AC: 8

ExAC AF: 0.00119 AC: 144

EpiCase AF: 0.000763

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2016	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 19, 2015

p.Gln345Lys in exon 7 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.2% (135/66722) of European chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201236317), and the glutamine (Gln) residue at position 345 is not evol utionarily conserved across species, with many species having a lysine (Lys) at this position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.071	T;T
Eigen	Benign	-0.068
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.016	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.76	D
PrimateAI	Benign	0.37	T
Polyphen		0.031	B;B
Vest4		0.24
MVP		0.39
MPC		0.11
ClinPred		0.025	T
GERP RS		5.7
Varity_R		0.23
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs201236317; hg19: chr5-89923388;