rs747160949
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206933.4(USH2A):c.14977_14978del(p.Phe4993ProfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F4993F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_206933.4 frameshift
Scores
Clinical Significance
Conservation
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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.14977_14978del | p.Phe4993ProfsTer7 | frameshift_variant | 69/72 | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.14977_14978del | p.Phe4993ProfsTer7 | frameshift_variant | 69/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000674083.1 | c.14977_14978del | p.Phe4993ProfsTer7 | frameshift_variant | 69/73 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251338Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135820
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461846Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727222
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Retinitis pigmentosa 39 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 06, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 29, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change creates a premature translational stop signal (p.Phe4993Profs*7) 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 (rs747160949, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with Usher syndrome (PMID: 27460420, 28127548). ClinVar contains an entry for this variant (Variation ID: 555201). 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. - |
Usher syndrome type 2A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 04, 2023 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 07, 2019 | - - |
Retinitis pigmentosa Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The p.Phe4993ProfsTer7 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, PM3-P. Based on this evidence we have classified this variant as 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