5-90558829-A-T

Position:

• chr5-90558829-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032119.4(ADGRV1):​c.-67A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,506,734 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (50 hom.)
• Consequence: ADGRV1 NM_032119.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.486

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-90558829-A-T is Benign according to our data. Variant chr5-90558829-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 908026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-90558829-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00221 (337/152152) while in subpopulation SAS AF= 0.0147 (71/4818). AF 95% confidence interval is 0.012. There are 3 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.-67A>T		5_prime_UTR_variant	1/90	ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.-67A>T		5_prime_UTR_variant	1/90	1	NM_032119.4	ENSP00000384582	P1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152034 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00511 AC: 804 AN: 157480 Hom.: 9 AF XY: 0.00617 AC XY: 516 AN XY: 83618

Gnomad AFR exome AF: 0.000364

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.0132

Gnomad EAS exome AF: 0.000174

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.0000665

Gnomad NFE exome AF: 0.00246

Gnomad OTH exome AF: 0.00973

GnomAD4 exome AF: 0.00291 AC: 3936 AN: 1354582 Hom.: 50 Cov.: 25 AF XY: 0.00338 AC XY: 2267 AN XY: 670834

Gnomad4 AFR exome AF: 0.000613

Gnomad4 AMR exome AF: 0.00338

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.0000832

Gnomad4 SAS exome AF: 0.0167

Gnomad4 FIN exome AF: 0.000143

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.00537

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152152 Hom.: 3 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74394

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0147

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00352 Hom.: 1

Bravo AF: 0.00197

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 2C Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.9
DANN	Benign	0.49

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: rs150816712; hg19: chr5-89854646;