rs541344995
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_206933.4(USH2A):c.8845+6_8845+9del variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000092 ( 0 hom. )
Consequence
USH2A
NM_206933.4 splice_donor_region, intron
NM_206933.4 splice_donor_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.69
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 Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.8845+6_8845+9del | splice_donor_region_variant, intron_variant | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.8845+6_8845+9del | splice_donor_region_variant, intron_variant | 1 | NM_206933.4 | P1 | |||
USH2A | ENST00000674083.1 | c.8845+6_8845+9del | splice_donor_region_variant, intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000572 AC: 87AN: 152104Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000207 AC: 52AN: 251314Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135826
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GnomAD4 exome AF: 0.0000924 AC: 135AN: 1461826Hom.: 0 AF XY: 0.0000646 AC XY: 47AN XY: 727222
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GnomAD4 genome ? AF: 0.000572 AC: 87AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33AN XY: 74428
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Usher syndrome type 2A Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 26, 2015 | Variant classified as Uncertain Significance - Favor Benign. The c.8845+6_8845+9 delTAAG variant in USH2A has not been previously reported in individuals with he aring loss. This variant has been identified in 0.2% (16/10578) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs541344995). Although this variant has been seen in the general popul ation, its frequency is not high enough to rule out a pathogenic role. This vari ant is located in the 5' splice region. Computational tools do not suggest an im pact to splicing at the native 5' donor splice site. However, this information i s not predictive enough to rule out pathogenicity. In summary, while the clinica l significance of the c.8845+6_8845+9delTAAG variant is uncertain, the frequency data suggest that it is more likely to be benign. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change falls in intron 44 of the USH2A gene. It does not directly change the encoded amino acid sequence of the USH2A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs541344995, gnomAD 0.2%). 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: 229628). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Retinitis pigmentosa 39 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
USH2A-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 10, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 24
Find out detailed SpliceAI scores and Pangolin per-transcript scores at