rs373391623

chr5-90805341-G-Achr5-90805341-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_032119.4(ADGRV1):c.14719G>A(p.Val4907Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,314 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4907A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.32

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12659663).
• BP6: Variant 5-90805341-G-A is Benign according to our data. Variant chr5-90805341-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505239.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.14719G>A	p.Val4907Ile	missense_variant	72/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.14719G>A	p.Val4907Ile	missense_variant	72/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.00

GnomAD3 exomes AF: 0.0000281 AC: 7 AN: 248956 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135034

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1460138 Hom.: 0 Cov.: 30 AF XY: 0.0000151 AC XY: 11 AN XY: 726318

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000458

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: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.0000331 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 21, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Val4907Ile va riant in GPR98 has not been previously reported in individuals with hearing loss or Usher syndrome, but it has been identified in 2/8614 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs373391623). Although this variant has been seen in the general population, it s frequency is not high enough to rule out a pathogenic role. The valine (Val) a t position 4907 is not highly conserved in mammals and evolutionary distant spec ies. Of note, 1 mammal (Golden hamster) has an isoleucine (Ile) despite high nea rby amino acid conservation, suggesting that this change at this position may be tolerated. Computational prediction tools and conservation analyses suggest th at this variant may not impact the protein, though this information is not predi ctive enough to rule out pathogenicity. In summary, while the clinical significa nce of the p.Val4907Ile variant is uncertain, these data suggest that it is more likely to be benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	13
Dann	Benign	0.91
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
Polyphen		0.51	P;P;.
Vest4		0.19
MutPred		0.34		Loss of catalytic residue at V4907 (P = 0.0861);Loss of catalytic residue at V4907 (P = 0.0861);.;
MVP		0.31
MPC		0.12
ClinPred		0.059	T
GERP RS		4.0
Varity_R		0.035
gMVP		0.25

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: rs373391623; hg19: chr5-90101158;