rs201481219

Positions:

chr5-90716735-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_032119.4(ADGRV1):c.9447+6G>A variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.000716 in 1,602,634 control chromosomes in the GnomAD database, including 4 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 0.00090 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 3 hom. )

Consequence

ADGRV1
NM_032119.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.0007103

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 4.00

Variant links:

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 links:

LOC105379077 (HGNC:):

LOC105379077 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 5-90716735-G-A is Benign according to our data. Variant chr5-90716735-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163588.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=2}. Variant chr5-90716735-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000697 (1011/1450310) while in subpopulation MID AF= 0.0135 (77/5698). AF 95% confidence interval is 0.0111. There are 3 homozygotes in gnomad4_exome. There are 492 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4 linkuse as main transcript	c.9447+6G>A		splice_donor_region_variant, intron_variant		ENST00000405460.9	NP_115495.3
LOC105379077	XR_001742802.2 linkuse as main transcript	n.364-926C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9 linkuse as main transcript	c.9447+6G>A		splice_donor_region_variant, intron_variant		1	NM_032119.4	ENSP00000384582	P1	Q8WXG9-1

Frequencies

GnomAD3 genomes

AF:

0.000900

AC:

137

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.000906

AC:

223

AN:

246084

Hom.:

AF XY:

0.000883

AC XY:

118

AN XY:

133562

show subpopulations

Gnomad AFR exome

AF:

0.000907

Gnomad AMR exome

AF:

0.00215

Gnomad ASJ exome

AF:

0.00304

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000433

Gnomad FIN exome

AF:

0.0000469

Gnomad NFE exome

AF:

0.000779

Gnomad OTH exome

AF:

0.000841

GnomAD4 exome

AF:

0.000697

AC:

1011

AN:

1450310

Hom.:

Cov.:

AF XY:

0.000682

AC XY:

492

AN XY:

721530

show subpopulations

Gnomad4 AFR exome

AF:

0.000513

Gnomad4 AMR exome

AF:

0.00204

Gnomad4 ASJ exome

AF:

0.00220

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000518

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000586

Gnomad4 OTH exome

AF:

0.00130

GnomAD4 genome

AF:

0.000899

AC:

137

AN:

152324

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.00119

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ADGRV1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 11, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ADGRV1 c.9447+6G>A variant was not identified in the literature but was identified in dbSNP (ID: rs201481219) and ClinVar (classified as a VUS by EGL Genetics and as likely benign by Laboratory for Molecular Medicine and Division of Genomic Diagnostics at The Children's Hospital of Philadelphia). The variant was also identified in control databases in 246 of 277482 chromosomes at a frequency of 0.000887 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 32 of 10164 chromosomes (freq: 0.003148), Latino in 78 of 34728 chromosomes (freq: 0.002246), Other in 7 of 7030 chromosomes (freq: 0.000996), African in 19 of 24152 chromosomes (freq: 0.000787), European (non-Finnish) in 96 of 127122 chromosomes (freq: 0.000755), South Asian in 13 of 30042 chromosomes (freq: 0.000433) and European (Finnish) in 1 of 24812 chromosomes (freq: 0.00004), but was not observed in the East Asian population. The c.9447+6G>A variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. However this splicing prediction has not been confirmed by RNA analysis. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2015	c.9447+6G>A in intron 6 of GPR98: This variant is not expected to have clinical significance because it has been identified in 0.3% (32/11530) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201481219). -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 31, 2015	- -

Usher syndrome type 2C

Uncertain:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00071

dbscSNV1_RF

Benign

0.042

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over