5-90692647-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.6994A>T(p.Ile2332Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,611,626 control chromosomes in the GnomAD database, including 1 homozygotes. 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. I2332T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 0.390

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=0.021339357).
• BP6: Variant 5-90692647-A-T is Benign according to our data. Variant chr5-90692647-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46359.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5, Benign=2}. Variant chr5-90692647-A-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.6994A>T	p.Ile2332Phe	missense_variant	32/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.6994A>T	p.Ile2332Phe	missense_variant	32/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.000281 AC: 69 AN: 245420 Hom.: 0 AF XY: 0.000278 AC XY: 37 AN XY: 133156

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000238

Gnomad ASJ exome AF: 0.00271

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000846

GnomAD4 exome AF: 0.000254 AC: 370 AN: 1459384 Hom.: 1 Cov.: 32 AF XY: 0.000266 AC XY: 193 AN XY: 725822

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.000609

Gnomad4 ASJ exome AF: 0.00330

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.000680

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.000484 AC XY: 36 AN XY: 74436

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.000372 Hom.: 1

Bravo AF: 0.000620

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.000207 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 29, 2017	The ADGRV1 p.Ile2332Phe variant (rs193030567) was reported in one individual with a diagnosis of Usher syndrome type 2C who also harbored the p.Val617Met variant (Sloan-Heggen 2016). The p.Ile2332Phe variant is listed in the Genome Aggregation Database (gnomAD) with an allele frequency of 0.3 percent in the Ashkenazi Jewish population (identified on 28 out of 10,072 chromosomes) and has been reported to the ClinVar database (Variation ID: 46359). The isoleucine at position 2332 is highly conserved considering 12 species up to zebrafish (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the ADGRV1 protein (SIFT: damaging, MutationTaster: disease causing, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.Ile2332Phe variant with certainty. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2020	This variant is associated with the following publications: (PMID: 26969326) -

Usher syndrome type 2C Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	research	DECIPHERD-UDD, Universidad del Desarrollo	Jul 01, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2017

p.Ile2332Phe in exon 32 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.3% (28/10072) of Ashkenazi Jewi sh chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs193030567). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.25	T
Polyphen		0.95	P;P;.
Vest4		0.84
MVP		0.64
MPC		0.36
ClinPred		0.28	T
GERP RS		3.4
Varity_R		0.48
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs193030567; hg19: chr5-89988464;