NM_032119.4:c.12631C>T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_032119.4(ADGRV1):c.12631C>T(p.Arg4211*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000556 in 1,439,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_032119.4 stop_gained
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
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000953 AC: 2AN: 209970 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000556 AC: 8AN: 1439158Hom.: 0 Cov.: 31 AF XY: 0.00000701 AC XY: 5AN XY: 713612 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg4211*) in the ADGRV1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ADGRV1 are known to be pathogenic (PMID: 19357117, 22135276, 22147658, 26226137, 30718709, 31047384, 32467589). This variant is present in population databases (rs727504777, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 33724713). ClinVar contains an entry for this variant (Variation ID: 179305). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Febrile seizures, familial, 4;C2931213:Usher syndrome type 2C Pathogenic:1
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Rare genetic deafness Pathogenic:1
The Arg4211X variant in GPR98 has not been reported in individuals with hearing loss or in large population studies. This nonsense variant leads to a premature termination codon at position 4211, which is predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at