chr1-215790293-A-C
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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.9959-11T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,612,948 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0066 ( 9 hom., cov: 32)
Exomes 𝑓: 0.00063 ( 15 hom. )
Consequence
USH2A
NM_206933.4 splice_polypyrimidine_tract, intron
NM_206933.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9824
2
Clinical Significance
Conservation
PhyloP100: 2.73
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 1-215790293-A-C is Benign according to our data. Variant chr1-215790293-A-C is described in ClinVar as [Benign]. Clinvar id is 48636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215790293-A-C is described in Lovd as [Likely_benign]. Variant chr1-215790293-A-C is described in Lovd as [Benign]. Variant chr1-215790293-A-C is described in Lovd as [Likely_pathogenic].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0066 (1005/152310) while in subpopulation AFR AF= 0.0227 (944/41570). AF 95% confidence interval is 0.0215. There are 9 homozygotes in gnomad4. There are 452 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 9 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.9959-11T>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.9959-11T>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_206933.4 | P1 | |||
USH2A | ENST00000674083.1 | c.9959-11T>G | splice_polypyrimidine_tract_variant, intron_variant |
Frequencies
GnomAD3 genomes AF: 0.00657 AC: 1000AN: 152192Hom.: 9 Cov.: 32
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GnomAD3 exomes AF: 0.00166 AC: 414AN: 249466Hom.: 9 AF XY: 0.00122 AC XY: 165AN XY: 135116
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GnomAD4 exome AF: 0.000628 AC: 918AN: 1460638Hom.: 15 Cov.: 31 AF XY: 0.000526 AC XY: 382AN XY: 726732
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GnomAD4 genome AF: 0.00660 AC: 1005AN: 152310Hom.: 9 Cov.: 32 AF XY: 0.00607 AC XY: 452AN XY: 74470
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2012 | 9959-11T>G in Intron 50 of USH2A: This variant is not expected to have clinical significance because it has been identified in 2.1% (80/3734) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs116150014). - |
Retinitis pigmentosa 39 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Usher syndrome type 2A Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -11
Find out detailed SpliceAI scores and Pangolin per-transcript scores at