rs201481219

Variant names:

• chr5-90716735-G-A
• rs201481219
• NM_032119.4:c.9447+6G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-90716735-G-A
• chr5-90716735-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_032119.4(ADGRV1):​c.9447+6G>A variant causes a splice 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. 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 0.00090 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (3 hom.)
• Consequence: ADGRV1 NM_032119.4 splice_region, intron
• Scores: Splicing: ADA: 0.0007103
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 4.00
• 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

LOC105379077 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 163588.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 492 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	NM_032119.4	MANE Select	c.9447+6G>A		splice_region intron	N/A	NP_115495.3
	ADGRV1	NR_003149.2		n.9463+6G>A		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.9447+6G>A		splice_region intron	N/A	ENSP00000384582.2
	ADGRV1	ENST00000509621.1	TSL:1	n.2144+6G>A		splice_region intron	N/A
	ADGRV1	ENST00000639473.1	TSL:5	n.4912G>A		non_coding_transcript_exon	Exon 23 of 23

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152206 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.000906 AC: 223 AN: 246084 AF XY: 0.000883

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 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.: 3 Cov.: 28 AF XY: 0.000682 AC XY: 492 AN XY: 721530

African (AFR) AF: 0.000513 AC: 17 AN: 33158

American (AMR) AF: 0.00204 AC: 90 AN: 44200

Ashkenazi Jewish (ASJ) AF: 0.00220 AC: 57 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.000518 AC: 44 AN: 84948

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 53020

Middle Eastern (MID) AF: 0.0135 AC: 77 AN: 5698

European-Non Finnish (NFE) AF: 0.000586 AC: 647 AN: 1103938

Other (OTH) AF: 0.00130 AC: 78 AN: 59874

GnomAD4 genome AF: 0.000899 AC: 137 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74480

African (AFR) AF: 0.000674 AC: 28 AN: 41572

American (AMR) AF: 0.00294 AC: 45 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.00119

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	-	3	not specified (3)
-	1	-	Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.64
PhyloP100		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs201481219; hg19: chr5-90012552;