NM_032119.4:c.8386G>C

Variant names:

• chr5-90704488-G-C
• rs1554088629
• NM_032119.4:c.8386G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032119.4(ADGRV1):​c.8386G>C​(p.Gly2796Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADGRV1 NM_032119.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.72
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.8386G>C	p.Gly2796Arg	missense splice_region	Exon 36 of 90	NP_115495.3
	ADGRV1	NR_003149.2		n.8402G>C		splice_region non_coding_transcript_exon	Exon 36 of 90

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRV1	ENST00000405460.9	TSL:1 MANE Select	c.8386G>C	p.Gly2796Arg	missense splice_region	Exon 36 of 90	ENSP00000384582.2
	ADGRV1	ENST00000509621.1	TSL:1	n.1083G>C		splice_region non_coding_transcript_exon	Exon 4 of 26
	ADGRV1	ENST00000640403.1	TSL:5	c.5677G>C	p.Gly1893Arg	missense splice_region	Exon 26 of 29	ENSP00000492531.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1358944 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 671968

African (AFR) AF: 0.00 AC: 0 AN: 30996

American (AMR) AF: 0.00 AC: 0 AN: 35822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24850

East Asian (EAS) AF: 0.00 AC: 0 AN: 36680

South Asian (SAS) AF: 0.00 AC: 0 AN: 74464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1043174

Other (OTH) AF: 0.00 AC: 0 AN: 56950

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly2796Arg variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome, or in large population studies. Computati onal prediction tools and conservation analyses suggest that this variant may im pact the protein, though this information is not predictive enough to determine pathogenicity. This variant is located in the last base of the exon, which is pa rt of the 5' splice region. Computational tools suggest a possible impact to spl icing. However, this information is not predictive enough to determine pathogeni city. In summary, the clinical significance of this variant is uncertain.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.29	T
PhyloP100		7.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.46		Loss of catalytic residue at V2797 (P = 0.0482)
MVP		0.75
MPC		0.35
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.70
gMVP		0.86
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.75		Position offset: 0

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

Other links and lift over

dbSNP: rs1554088629; hg19: chr5-90000305;