5-90653278-A-G
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.
The NM_032119.4(ADGRV1):c.3704A>G(p.Asn1235Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1235D) has been classified as Uncertain significance.
Frequency
Consequence
NM_032119.4 missense
Scores
Clinical Significance
Conservation
Publications
- Usher syndrome type 2Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Usher syndrome type 2CInheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
- febrile seizures, familial, 4Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- nonsyndromic genetic hearing lossInheritance: AR Classification: NO_KNOWN Submitted by: ClinGen
Genome browser will be placed here
ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ADGRV1 | ENST00000405460.9 | c.3704A>G | p.Asn1235Ser | missense_variant | Exon 20 of 90 | 1 | NM_032119.4 | ENSP00000384582.2 | ||
ADGRV1 | ENST00000640403.1 | c.995A>G | p.Asn332Ser | missense_variant | Exon 10 of 29 | 5 | ENSP00000492531.1 | |||
ADGRV1 | ENST00000504142.2 | n.2470A>G | non_coding_transcript_exon_variant | Exon 14 of 14 | 5 | |||||
ADGRV1 | ENST00000639676.1 | n.1302A>G | non_coding_transcript_exon_variant | Exon 8 of 11 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000402 AC: 1AN: 248966 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461626Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727088 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74384 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1235 of the ADGRV1 protein (p.Asn1235Ser). This variant is present in population databases (rs746622083, gnomAD 0.003%). 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: 505432). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ADGRV1 protein function with a negative predictive value of 95%. 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. -
not specified Uncertain:1
The p.Asn1235Ser variant in GPR98 has not been previously reported in individual s with hearing loss or Usher syndrome, but has been identified in 1/11278 of Lat ino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinst itute.org; dbSNP rs746622083). However, this frequency is not high enough to rul e out a pathogenic role. Computational prediction tools and conservation analysi s do not provide strong support for or against an impact to the protein. In summ ary, the clinical significance of the p.Asn1235Ser is uncertain. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at