5-90629203-A-T

Variant names:

• chr5-90629203-A-T
• rs182260529
• NM_032119.4:c.1510-7A>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_032119.4(ADGRV1):​c.1510-7A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00035 in 1,492,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: ADGRV1 NM_032119.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003562
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.494
• Publications: 0 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 5-90629203-A-T is Benign according to our data. Variant chr5-90629203-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180124.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032119.4. 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.1510-7A>T		splice_region intron	N/A	NP_115495.3
	ADGRV1	NR_003149.2		n.1609-7A>T		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.1510-7A>T		splice_region intron	N/A	ENSP00000384582.2
	ADGRV1	ENST00000504142.2	TSL:5	n.276-7A>T		splice_region intron	N/A
	ADGRV1	ENST00000640109.1	TSL:5	n.1606-7A>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152030 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000288 AC: 57 AN: 197836 AF XY: 0.000232

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000106

Gnomad NFE exome AF: 0.000406

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.000329 AC: 441 AN: 1340508 Hom.: 0 Cov.: 25 AF XY: 0.000320 AC XY: 211 AN XY: 658976

African (AFR) AF: 0.0000668 AC: 2 AN: 29946

American (AMR) AF: 0.000800 AC: 24 AN: 29986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21846

East Asian (EAS) AF: 0.00 AC: 0 AN: 38496

South Asian (SAS) AF: 0.00 AC: 0 AN: 63872

European-Finnish (FIN) AF: 0.000101 AC: 5 AN: 49388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5332

European-Non Finnish (NFE) AF: 0.000368 AC: 385 AN: 1046322

Other (OTH) AF: 0.000452 AC: 25 AN: 55320

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152148 Hom.: 0 Cov.: 31 AF XY: 0.000538 AC XY: 40 AN XY: 74378

African (AFR) AF: 0.000120 AC: 5 AN: 41514

American (AMR) AF: 0.00386 AC: 59 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68004

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.000211 Hom.: 0

Bravo AF: 0.000880

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	ADGRV1-related disorder (1)
-	-	1	not specified (1)
-	1	-	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.91
DANN	Benign	0.74
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs182260529; hg19: chr5-89925020;