rs57754754
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP6_Very_Strong
The NM_206933.4(USH2A):c.15297+3A>G 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 0.000584 in 1,614,204 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.0030 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 5 hom. )
Consequence
USH2A
NM_206933.4 splice_donor_region, intron
NM_206933.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9676
2
Clinical Significance
Conservation
PhyloP100: 1.98
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 -7 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
?
Variant 1-215634456-T-C is Benign according to our data. Variant chr1-215634456-T-C is described in ClinVar as [Benign]. Clinvar id is 48459.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr1-215634456-T-C is described in Lovd as [Likely_benign]. Variant chr1-215634456-T-C is described in Lovd as [Benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.15297+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.15297+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_206933.4 | P1 | |||
USH2A | ENST00000674083.1 | c.15297+3A>G | splice_donor_region_variant, intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00302 AC: 459AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000823 AC: 207AN: 251408Hom.: 1 AF XY: 0.000648 AC XY: 88AN XY: 135878
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GnomAD4 exome AF: 0.000331 AC: 484AN: 1461878Hom.: 5 Cov.: 31 AF XY: 0.000267 AC XY: 194AN XY: 727242
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GnomAD4 genome ? AF: 0.00301 AC: 459AN: 152326Hom.: 0 Cov.: 32 AF XY: 0.00289 AC XY: 215AN XY: 74496
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ClinVar
Significance: Benign
Submissions summary: Benign:6
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 21, 2019 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 25, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 15, 2012 | 15297+3A>G in Intron 70 of USH2A: This variant is not expected to have clinical significance because it has been identified in 1.0% (37/3738) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs57754754). - |
Usher syndrome Benign:1
Benign, reviewed by expert panel | curation | ClinGen Hearing Loss Variant Curation Expert Panel | Sep 14, 2018 | The filtering allele frequency of the c.15297+3A>G variant in the USH2A gene is 0.99% (265/24032) of African chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). - |
Computational scores
Source:
Name
Calibrated prediction
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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