rs727504667
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_005709.4(USH1C):c.1284+4C>T 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 0.0000355 in 1,577,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000037 ( 0 hom. )
Consequence
USH1C
NM_005709.4 splice_donor_region, intron
NM_005709.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0001652
2
Clinical Significance
Conservation
PhyloP100: 0.600
Genes affected
USH1C (HGNC:12597): (USH1 protein network component harmonin) This gene encodes a scaffold protein that functions in the assembly of Usher protein complexes. The protein contains PDZ domains, a coiled-coil region with a bipartite nuclear localization signal and a PEST degradation sequence. Defects in this gene are the cause of Usher syndrome type 1C and non-syndromic sensorineural deafness autosomal recessive type 18. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.46).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
USH1C | NM_005709.4 | c.1284+4C>T | splice_donor_region_variant, intron_variant | ENST00000318024.9 | |||
USH1C | NM_153676.4 | c.1211-1107C>T | intron_variant | ENST00000005226.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
USH1C | ENST00000005226.12 | c.1211-1107C>T | intron_variant | 5 | NM_153676.4 | ||||
USH1C | ENST00000318024.9 | c.1284+4C>T | splice_donor_region_variant, intron_variant | 1 | NM_005709.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000714 AC: 14AN: 195972Hom.: 0 AF XY: 0.000124 AC XY: 13AN XY: 104692
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GnomAD4 exome AF: 0.0000372 AC: 53AN: 1425630Hom.: 0 Cov.: 32 AF XY: 0.0000553 AC XY: 39AN XY: 705586
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74480
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 16, 2013 | Variant classified as Uncertain Significance - Favor Benign. The 1284+4C>T varia nt in USH1C has not been reported in individuals with hearing loss or in large p opulation studies. This variant is located in the 5' splice region. Computationa l tools do not suggest an impact to splicing. However, this information is not p redictive enough to rule out pathogenicity. Although position +4 is part of the splice site region, the reference sequence was already divergent from consensus (normally an A at this position) and therefore this variant is less likely to di srupt splicing. In summary, the clinical significance of this variant cannot be determined with certainty; however based upon the arguments described above, we would lean towards a more likely benign role. - |
Usher syndrome type 1C Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
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DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at