NM_206933.4:c.8845+6_8845+9delTAAG
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+9delTAAG variant causes a splice 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 Uncertain significance (★★).
Frequency
Consequence
NM_206933.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.8845+6_8845+9delTAAG | splice_region_variant, intron_variant | Intron 44 of 71 | 1 | NM_206933.4 | ENSP00000305941.3 | |||
USH2A | ENST00000674083.1 | c.8845+6_8845+9delTAAG | splice_region_variant, intron_variant | Intron 44 of 72 | ENSP00000501296.1 |
Frequencies
GnomAD3 genomes AF: 0.000572 AC: 87AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000207 AC: 52AN: 251314Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135826
GnomAD4 exome AF: 0.0000924 AC: 135AN: 1461826Hom.: 0 AF XY: 0.0000646 AC XY: 47AN XY: 727222
GnomAD4 genome AF: 0.000572 AC: 87AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33AN XY: 74428
ClinVar
Submissions by phenotype
Usher syndrome type 2A Uncertain:2
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not specified Uncertain:1
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
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 been observed in individual(s) with retinitis pigmentosa (PMID: 36819107). 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
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USH2A-related disorder Benign:1
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at