5-90706400-ACT-A

Variant names:

• chr5-90706400-ACT-A
• rs780180737
• NM_032119.4:c.8730+9_8730+10delCT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000405460.9(ADGRV1):​c.8730+7_8730+8delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,485,070 control chromosomes in the GnomAD database, including 12 homozygotes. 1/1 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 0.0032 (9 hom., cov: 30)
  • Exomes 𝑓: 0.00092 (3 hom.)
• Consequence: ADGRV1 ENST00000405460.9 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0200
• 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: Orphanet, ClinGen
• Usher syndrome type 2C

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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: Benign. The variant received -9 ACMG points.

• BP6: Variant 5-90706400-ACT-A is Benign according to our data. Variant chr5-90706400-ACT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46398.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0881 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000405460.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.8730+9_8730+10delCT		intron	N/A	NP_115495.3	Q8WXG9-1
	ADGRV1	NR_003149.2		n.8746+9_8746+10delCT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.8730+7_8730+8delCT		splice_region intron	N/A	ENSP00000384582.2	Q8WXG9-1
	ADGRV1	ENST00000509621.1	TSL:1	n.1427+7_1427+8delCT		splice_region intron	N/A
	ADGRV1	ENST00000640403.1	TSL:5	c.6021+7_6021+8delCT		splice_region intron	N/A	ENSP00000492531.1	A0A1W2PRC7

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 263 AN: 81038 Hom.: 9 Cov.: 30

Gnomad AFR AF: 0.000256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00240

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0986

Gnomad SAS AF: 0.00308

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000226

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00515 AC: 648 AN: 125930 AF XY: 0.00477

Gnomad AFR exome AF: 0.000278

Gnomad AMR exome AF: 0.000196

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0765

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00256

GnomAD4 exome AF: 0.000925 AC: 1298 AN: 1403996 Hom.: 3 AF XY: 0.000903 AC XY: 628 AN XY: 695212

African (AFR) AF: 0.000164 AC: 5 AN: 30464

American (AMR) AF: 0.0000925 AC: 3 AN: 32424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24258

East Asian (EAS) AF: 0.0293 AC: 1118 AN: 38188

South Asian (SAS) AF: 0.000400 AC: 30 AN: 74938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51642

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5528

European-Non Finnish (NFE) AF: 0.0000129 AC: 14 AN: 1088516

Other (OTH) AF: 0.00219 AC: 127 AN: 58038

GnomAD4 genome AF: 0.00323 AC: 262 AN: 81074 Hom.: 9 Cov.: 30 AF XY: 0.00337 AC XY: 132 AN XY: 39212

African (AFR) AF: 0.000255 AC: 4 AN: 15686

American (AMR) AF: 0.00240 AC: 16 AN: 6674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2210

East Asian (EAS) AF: 0.0988 AC: 223 AN: 2258

South Asian (SAS) AF: 0.00308 AC: 7 AN: 2272

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 180

European-Non Finnish (NFE) AF: 0.0000226 AC: 1 AN: 44200

Other (OTH) AF: 0.00993 AC: 11 AN: 1108

Alfa AF: 0.000590 Hom.: 0

Asia WGS AF: 0.0130 AC: 44 AN: 3460

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	1	ADGRV1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.020
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs780180737; hg19: chr5-90002217;