rs117798425
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Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2
The NM_206933.4(USH2A):c.4758+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.000568 in 1,613,506 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00076 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00055 ( 10 hom. )
Consequence
USH2A
NM_206933.4 splice_donor_region, intron
NM_206933.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9624
2
Clinical Significance
Conservation
PhyloP100: 4.49
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 Benign. Variant got -15 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
BP6
?
Variant 1-216097080-T-C is Benign according to our data. Variant chr1-216097080-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 156396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216097080-T-C is described in Lovd as [Benign]. Variant chr1-216097080-T-C is described in Lovd as [Likely_benign]. Variant chr1-216097080-T-C is described in Lovd as [Likely_pathogenic]. Variant chr1-216097080-T-C is described in Lovd as [Pathogenic]. Variant chr1-216097080-T-C is described in Lovd as [Pathogenic]. Variant chr1-216097080-T-C is described in Lovd as [Likely_pathogenic].
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000761 (116/152358) while in subpopulation EAS AF= 0.0183 (95/5190). AF 95% confidence interval is 0.0153. There are 0 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 10 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.4758+3A>G | splice_donor_region_variant, intron_variant | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.4758+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_206933.4 | P1 | |||
USH2A | ENST00000674083.1 | c.4758+3A>G | splice_donor_region_variant, intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.000782 AC: 119AN: 152240Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00151 AC: 378AN: 249948Hom.: 5 AF XY: 0.00142 AC XY: 192AN XY: 135234
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GnomAD4 exome AF: 0.000548 AC: 801AN: 1461148Hom.: 10 Cov.: 31 AF XY: 0.000583 AC XY: 424AN XY: 726850
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GnomAD4 genome ? AF: 0.000761 AC: 116AN: 152358Hom.: 0 Cov.: 33 AF XY: 0.000966 AC XY: 72AN XY: 74508
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | USH2A: BS1 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 2018 | This variant is associated with the following publications: (PMID: 25445212, 25404053, 30245029, 29625443, 31180159, 31904091, 32090030, 32893482, 33090715) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Usher syndrome type 2A Benign:3
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 24, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 23, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 22, 2017 | c.4758+3A>G in intron 22 of USH2A: This variant is not expected to have clinical significance because it has been identified in 1.9% (348/18756) of East Asian c hromosomes, including 4 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs117798425). ACMG/AMP Criteria applie d: BA1. - |
Leber congenital amaurosis Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Molecular Diagnostics Laboratory, Seoul National University Hospital | Sep 18, 2014 | - - |
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 10, 2022 | - - |
Retinitis pigmentosa 39 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at