NM_032119.4:c.11581-3dupC

Variant names:

• chr5-90756446-T-TC
• rs34894132
• NM_032119.4:c.11581-3dupC

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_Moderate BP6_Very_Strong BA1

The NM_032119.4(ADGRV1):​c.11581-3dupC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 1,448,428 control chromosomes in the GnomAD database, including 128,976 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11886 hom., cov: 0)
  • Exomes 𝑓: 0.42 (117090 hom.)
• Consequence: ADGRV1 NM_032119.4 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.401
• Publications: 8 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: Benign. The variant received -14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.009354685 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: tttttcccccatccccccAGgat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 5-90756446-T-TC is Benign according to our data. Variant chr5-90756446-T-TC is described in ClinVar as Benign. ClinVar VariationId is 46256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

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.11581-3dupC		splice_acceptor intron	N/A	NP_115495.3
	ADGRV1	NR_003149.2		n.11597-3dupC		splice_acceptor intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.11581-8_11581-7insC		splice_region intron	N/A	ENSP00000384582.2
	ADGRV1	ENST00000509621.1	TSL:1	n.4278-8_4278-7insC		splice_region intron	N/A
	ADGRV1	ENST00000425867.3	TSL:5	c.712-533_712-532insC		intron	N/A	ENSP00000392618.3

Frequencies

GnomAD3 genomes AF: 0.380 AC: 57640 AN: 151804 Hom.: 11878 Cov.: 0

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.442

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.402 AC: 73922 AN: 183724 AF XY: 0.402

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.590

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.407

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.413

GnomAD4 exome AF: 0.417 AC: 540617 AN: 1296506 Hom.: 117090 Cov.: 29 AF XY: 0.414 AC XY: 263736 AN XY: 636982

African (AFR) AF: 0.194 AC: 5411 AN: 27958

American (AMR) AF: 0.578 AC: 15109 AN: 26154

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 6831 AN: 21440

East Asian (EAS) AF: 0.493 AC: 17506 AN: 35512

South Asian (SAS) AF: 0.330 AC: 19127 AN: 57900

European-Finnish (FIN) AF: 0.426 AC: 20601 AN: 48338

Middle Eastern (MID) AF: 0.374 AC: 1940 AN: 5190

European-Non Finnish (NFE) AF: 0.424 AC: 432559 AN: 1021058

Other (OTH) AF: 0.407 AC: 21533 AN: 52956

GnomAD4 genome AF: 0.380 AC: 57664 AN: 151922 Hom.: 11886 Cov.: 0 AF XY: 0.383 AC XY: 28432 AN XY: 74236

African (AFR) AF: 0.213 AC: 8855 AN: 41478

American (AMR) AF: 0.540 AC: 8236 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1171 AN: 3462

East Asian (EAS) AF: 0.481 AC: 2489 AN: 5172

South Asian (SAS) AF: 0.380 AC: 1826 AN: 4808

European-Finnish (FIN) AF: 0.442 AC: 4655 AN: 10528

Middle Eastern (MID) AF: 0.366 AC: 107 AN: 292

European-Non Finnish (NFE) AF: 0.429 AC: 29121 AN: 67916

Other (OTH) AF: 0.417 AC: 879 AN: 2106

Alfa AF: 0.363 Hom.: 1767

Bravo AF: 0.382

Asia WGS AF: 0.431 AC: 1498 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 08, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

11581-3_11581-2insC in intron 55 of GPR98: This variant is not expected to have clinical significance because it has been found frequently in the general popula tion (rs34894132 - 7 entries) and in 9/13 cases from our laboratory.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 22, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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: rs34894132; hg19: chr5-90052263;