rs1553261478
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_ModeratePM2PP3_StrongPP5
The NM_206933.4(USH2A):c.10388-1G>C variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
USH2A
NM_206933.4 splice_acceptor
NM_206933.4 splice_acceptor
Scores
3
2
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.06
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 Likely_pathogenic. Variant got 9 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.012620924 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 1-215782936-C-G is Pathogenic according to our data. Variant chr1-215782936-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 522485.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH2A | NM_206933.4 | c.10388-1G>C | splice_acceptor_variant | ENST00000307340.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH2A | ENST00000307340.8 | c.10388-1G>C | splice_acceptor_variant | 1 | NM_206933.4 | P1 | |||
USH2A | ENST00000674083.1 | c.10388-1G>C | splice_acceptor_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | Sep 18, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Benign
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -15
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at