rs201416399

Positions:

• chr5-90810437-G-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.15177G>T​(p.Gln5059His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,862 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 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.728

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=0.009639651).
• BP6: Variant 5-90810437-G-T is Benign according to our data. Variant chr5-90810437-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 289414.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRV1	NM_032119.4	c.15177G>T	p.Gln5059His	missense_variant	74/90	ENST00000405460.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRV1	ENST00000405460.9	c.15177G>T	p.Gln5059His	missense_variant	74/90	1	NM_032119.4	P1

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000153 AC: 38 AN: 248768 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 134978

Gnomad AFR exome AF: 0.00214

Gnomad AMR exome AF: 0.000116

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: 0.000166

GnomAD4 exome AF: 0.0000541 AC: 79 AN: 1461538 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727058

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.000179

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: 0.00

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74494

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.000620

ESP6500AA AF: 0.00191 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000166 AC: 20

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 24, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 12, 2017

p.Gln5059His 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, three mammals (Alpaca, Bactrian camel, Cape elephant shrew) have a histid ine (His) at this position. It has been identified in 0.2% (16/9634) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs201416399). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.1
DANN	Benign	0.72
DEOGEN2	Benign	0.081	T;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.63	.;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.3	.;N;.
REVEL	Benign	0.013
Sift	Benign	0.17	.;T;.
Sift4G	Benign	0.55	.;T;.
Polyphen		0.12	B;B;.
Vest4		0.081
MutPred		0.37		Gain of catalytic residue at N5060 (P = 0.0871);Gain of catalytic residue at N5060 (P = 0.0871);.;
MVP		0.25
MPC		0.10
ClinPred		0.022	T
GERP RS		0.18
Varity_R		0.048
gMVP		0.43

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: rs201416399; hg19: chr5-90106254;