rs556550485
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_004100.5(EYA4):c.723A>G(p.Pro241=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000136 in 1,613,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_004100.5 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EYA4 | NM_004100.5 | c.723A>G | p.Pro241= | splice_region_variant, synonymous_variant | 9/20 | ENST00000355286.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EYA4 | ENST00000355286.12 | c.723A>G | p.Pro241= | splice_region_variant, synonymous_variant | 9/20 | 1 | NM_004100.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250904Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135584
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461358Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726994
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74452
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 19, 2015 | Variant classified as Uncertain Significance - Favor Benign. The c.723A>G (p.Pro 241Pro) variant in EYA4 has not been previously reported in individuals with hea ring loss and was absent from large population studies. This variant is located in the last two bases of the exon, which is part of the 3? splice region. Comput ational tools do not predict altered splicing, and four species (rhesus, crab-ea ting macaque, baboon, green monkey) have guanine (G) at this nucleotide position . However, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the c.723A>G variant is uncertai n, the computational and conservation data suggests it is more likely to be beni gn. - |
Dilated cardiomyopathy 1J Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 228682). This variant has not been reported in the literature in individuals affected with EYA4-related conditions. This variant is present in population databases (rs556550485, gnomAD 0.007%). This sequence change affects codon 241 of the EYA4 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the EYA4 protein. It affects a nucleotide within the consensus splice site. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 28, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at