rs1554113222

Positions:

• chr5-90778613-T-TAA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000405460.9(ADGRV1):​c.12849+5_12849+6insAA variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGRV1 ENST00000405460.9 splice_donor_region, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.372

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRV1	NM_032119.4	c.12849+5_12849+6insAA		splice_donor_region_variant, intron_variant		ENST00000405460.9	NP_115495.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRV1	ENST00000405460.9	c.12849+5_12849+6insAA		splice_donor_region_variant, intron_variant		1	NM_032119.4	ENSP00000384582	P1
ADGRV1	ENST00000425867.3	c.1803+5_1803+6insAA		splice_donor_region_variant, intron_variant		5		ENSP00000392618
ADGRV1	ENST00000639431.1	c.265+102405_265+102406insAA		intron_variant, NMD_transcript_variant		5		ENSP00000491057
ADGRV1	ENST00000640464.1	n.3268+5_3268+6insAA		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 15, 2016

Variant classified as Uncertain Significance - Favor Pathogenic. The c.12849+5_1 2849+6insAA variant in GPR98 has been reported in the compound heterozygous stat e with a pathogenic GPR98 variant in one individual with hearing loss (this indi vidual's daughter). This variant has not been identified in large population st udies. This variant is located in the 5' splice region. Computational tools sugg est an impact to splicing; however, this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathog enic role, the clinical significance of the c.12849+5_12849+6insAA variant is un certain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 11, 2022

This sequence change falls in intron 63 of the ADGRV1 gene. It does not directly change the encoded amino acid sequence of the ADGRV1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ADGRV1-related conditions. ClinVar contains an entry for this variant (Variation ID: 504949). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554113222; hg19: chr5-90074430;