rs41303352

Positions:

• chr5-90683874-A-C
• chr5-90683874-A-G
• chr5-90683874-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_032119.4(ADGRV1):​c.5953A>C​(p.Asn1985His) variant causes a missense change. The variant allele was found at a frequency of 0.000174 in 1,613,072 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. N1985D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 4.02

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011920661).
• BP6: Variant 5-90683874-A-C is Benign according to our data. Variant chr5-90683874-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196141.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.5953A>C	p.Asn1985His	missense_variant	28/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.5953A>C	p.Asn1985His	missense_variant	28/90	1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes AF: 0.000744 AC: 113 AN: 151974 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000263 AC: 65 AN: 246954 Hom.: 0 AF XY: 0.000179 AC XY: 24 AN XY: 133932

Gnomad AFR exome AF: 0.00377

Gnomad AMR exome AF: 0.000146

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: 0.00000896

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1460980 Hom.: 0 Cov.: 51 AF XY: 0.0000908 AC XY: 66 AN XY: 726692

Gnomad4 AFR exome AF: 0.00385

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000756 AC: 115 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74348

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00000943 Hom.: 1149

ExAC AF: 0.000290 AC: 35

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 04, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 20, 2015

p.Asn1985His in exon 28 of GPR98: This variant is not expected to have clinical significance it has been identified in 0.32% (31/9680) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP r s41303352). -

ADGRV1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	.;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.65	D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	.;N;.
REVEL	Benign	0.12
Sift	Benign	0.030	.;D;.
Sift4G	Uncertain	0.026	.;D;.
Polyphen		0.88	P;P;.
Vest4		0.36
MVP		0.57
MPC		0.33
ClinPred		0.044	T
GERP RS		4.5
Varity_R		0.42
gMVP		0.50

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: rs41303352; hg19: chr5-89979691; COSMIC: COSV105343851;