chr5-90805383-G-A

Position:

• chr5-90805383-G-A

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.14761G>A​(p.Ala4921Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,610,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 0.654

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=0.029129028).
• BP6: Variant 5-90805383-G-A is Benign according to our data. Variant chr5-90805383-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178370.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr5-90805383-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.14761G>A	p.Ala4921Thr	missense_variant	72/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.14761G>A	p.Ala4921Thr	missense_variant	72/90	1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.000779

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000502 AC: 125 AN: 248982 Hom.: 0 AF XY: 0.000541 AC XY: 73 AN XY: 135060

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000815

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000798 AC: 1164 AN: 1458518 Hom.: 0 Cov.: 30 AF XY: 0.000775 AC XY: 562 AN XY: 725232

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000940

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.000943

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.000550 AC XY: 41 AN XY: 74504

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000719 Hom.: 0

Bravo AF: 0.000948

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000268 AC: 1

ESP6500EA AF: 0.000973 AC: 8

ExAC AF: 0.000406 AC: 49

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 20, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	The ADGRV1 c.14761G>A; p.Ala4921Thr variant (rs200115167), to our knowledge, has not been reported in the medical literature; however, it is listed in the ClinVar database with conflicting interpretations of pathogenicity (Variation ID: 178370). This variant is found in the general population with an allele frequency in non-Finnish European populations of 0.00% (101/128,320 alleles) in the Genome Aggregation Database. The alanine at codon 4921 is moderately conserved (Alamut v.2.11) and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, based on the available information, the clinical significance of this variant is uncertain. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.14761G>A (p.A4921T) alteration is located in exon 72 (coding exon 72) of the ADGRV1 gene. This alteration results from a G to A substitution at nucleotide position 14761, causing the alanine (A) at amino acid position 4921 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 24, 2013

Ala4921Thr in exon 72 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.1% (8/8218) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs200115167). Furthermore, this amino acid is not well conserved acr oss species and several mammals carry a threonine (Thr) at this position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.071	T;T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.60	.;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.029	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.32	.;N;.
REVEL	Benign	0.036
Sift	Benign	0.35	.;T;.
Sift4G	Benign	0.69	.;T;.
Polyphen		0.0010	B;B;.
Vest4		0.066
MVP		0.17
MPC		0.047
ClinPred		0.0066	T
GERP RS		1.4
Varity_R		0.029
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200115167; hg19: chr5-90101200;