rs768299251

Positions:

• chr5-90810979-C-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.15719C>T​(p.Thr5240Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,696 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.123

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]

ADGRV1 (HGNC:):

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=0.058783114).
• BP6: Variant 5-90810979-C-T is Benign according to our data. Variant chr5-90810979-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505258.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.15719C>T	p.Thr5240Ile	missense_variant	74/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.15719C>T	p.Thr5240Ile	missense_variant	74/90	1	NM_032119.4	ENSP00000384582.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248720 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 134936

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

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: 0.00

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461696 Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9 AN XY: 727130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

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: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2016

p.Thr5240Ile in exon 74 of GPR98: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, elephants and aardvarks have a threonine (Thr) at this position despite h igh nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has been identifie d in 2/11552 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.8
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.57	.;T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	.;N;.
REVEL	Benign	0.0080
Sift	Benign	0.24	.;T;.
Sift4G	Benign	0.12	.;T;.
Polyphen		0.0	B;B;.
Vest4		0.059
MutPred		0.42		Loss of disorder (P = 0.086);Loss of disorder (P = 0.086);.;
MVP		0.18
MPC		0.28
ClinPred		0.044	T
GERP RS		0.70
Varity_R		0.035
gMVP		0.36

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: rs768299251; hg19: chr5-90106796;