rs773996398

Variant names:

• chr5-90558869-CCGGCGGGGACCGCCGGGA-C
• rs773996398
• ENST00000640281.1:n.34_51delCGGCGGGGACCGCCGGGA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The ENST00000640281.1(ADGRV1):​n.34_51delCGGCGGGGACCGCCGGGA variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 1,559,994 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: ADGRV1 ENST00000640281.1 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 3.33
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Usher syndrome type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• febrile seizures, familial, 4

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000497 (70/1407810) while in subpopulation MID AF = 0.00514 (29/5646). AF 95% confidence interval is 0.00367. There are 0 homozygotes in GnomAdExome4. There are 31 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000640281.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.-26_-9delCGGCGGGGACCGCCGGGA		5_prime_UTR	Exon 1 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.74_91delCGGCGGGGACCGCCGGGA		non_coding_transcript_exon	Exon 1 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000640281.1	TSL:1	n.34_51delCGGCGGGGACCGCCGGGA		non_coding_transcript_exon	Exon 1 of 7
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.-26_-9delCGGCGGGGACCGCCGGGA		5_prime_UTR	Exon 1 of 90	ENSP00000384582.2
	ADGRV1	ENST00000638316.1	TSL:5	n.185_202delCGGCGGGGACCGCCGGGA		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000121 AC: 20 AN: 164926 AF XY: 0.000114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000755

Gnomad OTH exome AF: 0.00220

GnomAD4 exome AF: 0.0000497 AC: 70 AN: 1407810 Hom.: 0 AF XY: 0.0000446 AC XY: 31 AN XY: 695112

African (AFR) AF: 0.00 AC: 0 AN: 32414

American (AMR) AF: 0.000220 AC: 8 AN: 36434

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25246

East Asian (EAS) AF: 0.00 AC: 0 AN: 36988

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49316

Middle Eastern (MID) AF: 0.00514 AC: 29 AN: 5646

European-Non Finnish (NFE) AF: 0.0000194 AC: 21 AN: 1083258

Other (OTH) AF: 0.000171 AC: 10 AN: 58352

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74406

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.0000416

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ADGRV1-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=287/13	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773996398; hg19: chr5-89854686;