8-71321853-G-T
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000503.6(EYA1):c.299C>A(p.Thr100Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000503.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EYA1 | NM_000503.6 | c.299C>A | p.Thr100Asn | missense_variant | Exon 6 of 18 | ENST00000340726.8 | NP_000494.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251388Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135858
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727244
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152236Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74374
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The Thr100Asn varia nt in EYA1 has not been previously reported in individuals with hearing loss, bu t has been identified in 0.02% (1/4406) of African American chromosomes by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs373501 480). This frequency is not high enough to rule out pathogenicity. The threonin e (Thr) residue at position 100 is not completely conserved across species, with platypus and frog having an asparagine (Asn) at this position. In summary, addi tional information is needed to determine the clinical significance of this vari ant; however, we would lean towards a more likely benign role. -
Branchiootic syndrome 1 Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
EYA1-related disorder Uncertain:1
The EYA1 c.299C>A variant is predicted to result in the amino acid substitution p.Thr100Asn. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-72234088-G-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Otofaciocervical syndrome 1 Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at