rs397518048
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206933.4(USH2A):c.9424G>T(p.Gly3142Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,630 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_206933.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.9424G>T | p.Gly3142Ter | stop_gained | 48/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.9424G>T | p.Gly3142Ter | stop_gained | 48/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.9424G>T | p.Gly3142Ter | stop_gained | 48/73 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151908Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250190Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135168
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1460722Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6AN XY: 726672
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151908Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74172
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | USH2A: PM3:Very Strong, PVS1, PM2, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change creates a premature translational stop signal (p.Gly3142*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs397518048, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with Usher syndrome and inherited retinal degeneration (PMID: 17405132, 23591405, 28130426, 28653555). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48626). For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa 39 Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 27, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Usher syndrome type 2A Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 10, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Usher syndrome type 2 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Usher syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | Variant summary: USH2A c.9424G>T (p.Gly3142X) results in a premature termination codon and is predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 2.4e-05 in 250190 control chromosomes (gnomAD). c.9424G>T has been reported in the literature as a biallelic genotype in individuals affected with Usher Syndrome (e.g. Neuhaus_2017). These data indicate that the variant is very likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 28944237). Eleven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 03, 2015 | - - |
Usher syndrome;C5680250:Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 20, 2018 | The p.Gly3142X variant has been reported in 9 individuals with Usher syndrome, 4 patients with retinal dystrophy, and 1 patient with sensorineural hearing loss, and at least 10 of these individuals were compound heterozygous for a second pa thogenic USH2A variant (Baux 2007, Sandberg 2008, McGee 2010, Glockle 2013, Kraw itz 2014, Baux 2014, Lenarduzzi 2015, Lenassi 2015, Bonnet 2016, LMM data). This variant was identified in 0.005% (5/110538) of European chromosomes by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org); however, thi s frequency is low enough to be consistent with a recessive carrier frequency. T his nonsense variant leads to a premature termination codon at position 3142, wh ich is predicted to lead to a truncated or absent protein. In summary, this vari ant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the predicted impact of the variant, the reported compound het erozygous individuals with Usher syndrome, and its low frequency in the general population. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PM2, PP4. - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 04, 2021 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 11, 2019 | - - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The p.Gly3142Ter variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PVS1, PM2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at