rs397518012
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_206933.4(USH2A):c.3435del(p.Val1147SerfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1145P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
USH2A
NM_206933.4 frameshift
NM_206933.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.937
Genes affected
USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-216200002-CT-C is Pathogenic according to our data. Variant chr1-216200002-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 48502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.3435del | p.Val1147SerfsTer6 | frameshift_variant | 17/72 | ENST00000307340.8 | |
USH2A-AS1 | XR_922596.4 | n.691+4078del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.3435del | p.Val1147SerfsTer6 | frameshift_variant | 17/72 | 1 | NM_206933.4 | P1 | |
USH2A | ENST00000366942.3 | c.3435del | p.Val1147SerfsTer6 | frameshift_variant | 17/21 | 1 | |||
USH2A-AS1 | ENST00000420867.1 | n.363-4027del | intron_variant, non_coding_transcript_variant | 3 | |||||
USH2A | ENST00000674083.1 | c.3435del | p.Val1147SerfsTer6 | frameshift_variant | 17/73 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 05, 2023 | This sequence change creates a premature translational stop signal (p.Val1147Serfs*6) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with USH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 48502). For these reasons, this variant has been classified as Pathogenic. - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 19, 2010 | The Val1147fs variant in USH2A has not been reported in the literature nor previ ously identified by our laboratory. The Val1147fs variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1147 and leads to a premature stop codon 6 codons downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this varia nt meets our criteria to be classified as pathogenic. - |
Usher syndrome type 2A Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Sep 03, 2018 | - - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at