rs41311625

Positions:

• chr5-91153342-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032119.4(ADGRV1):​c.18746T>G​(p.Leu6249Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000987 in 1,612,498 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (6 hom.)
• Consequence: ADGRV1 NM_032119.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 5.50

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]

LUCAT1 (HGNC:48498): (lung cancer associated transcript 1)

LOC107986432 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069268346).
• BP6: Variant 5-91153342-T-G is Benign according to our data. Variant chr5-91153342-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46301.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr5-91153342-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00297 (452/152326) while in subpopulation AFR AF= 0.00823 (342/41568). AF 95% confidence interval is 0.00751. There are 1 homozygotes in gnomad4. There are 198 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.18746T>G	p.Leu6249Arg	missense_variant	89/90	ENST00000405460.9	NP_115495.3
LOC107986432	XR_001742795.2	n.1208-1154A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.18746T>G	p.Leu6249Arg	missense_variant	89/90	1	NM_032119.4	ENSP00000384582	P1
LUCAT1	ENST00000650150.1	n.380-1154A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152208 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00818

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00155 AC: 383 AN: 246748 Hom.: 2 AF XY: 0.00124 AC XY: 166 AN XY: 133864

Gnomad AFR exome AF: 0.00784

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00976

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000996

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000464

Gnomad OTH exome AF: 0.00484

GnomAD4 exome AF: 0.000781 AC: 1140 AN: 1460172 Hom.: 6 Cov.: 32 AF XY: 0.000739 AC XY: 537 AN XY: 726244

Gnomad4 AFR exome AF: 0.00777

Gnomad4 AMR exome AF: 0.00234

Gnomad4 ASJ exome AF: 0.00960

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000932

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000346

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152326 Hom.: 1 Cov.: 33 AF XY: 0.00266 AC XY: 198 AN XY: 74490

Gnomad4 AFR AF: 0.00823

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00109 Hom.: 1

Bravo AF: 0.00335

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00741 AC: 28

ESP6500EA AF: 0.000853 AC: 7

ExAC AF: 0.00142 AC: 171

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000601

EpiControl AF: 0.000477

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ADGRV1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 12, 2019	This variant is associated with the following publications: (PMID: 22135276, 26969326, 28322503, 31130284) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 15, 2012	Leu6249Arg in Exon 89 of GPR98: This variant is not expected to have clinical si gnificance because it has been identified in 0.8% (24/3090) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs41311625). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2016	- -

Usher syndrome type 2C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

ADGRV1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	.;T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0069	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.92	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.1	.;N;.;.
REVEL	Benign	0.25
Sift	Uncertain	0.0080	.;D;.;.
Sift4G	Uncertain	0.0030	.;D;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.76
MVP		0.74
MPC		0.34
ClinPred		0.032	T
GERP RS		4.9
Varity_R		0.38
gMVP		0.76

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: rs41311625; hg19: chr5-90449159;