rs201537030
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000503.6(EYA1):c.1699-8T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000861 in 1,608,878 control chromosomes in the GnomAD database, including 2 homozygotes. 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
Genomes: 𝑓 0.00053 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00090 ( 2 hom. )
Consequence
EYA1
NM_000503.6 splice_region, splice_polypyrimidine_tract, intron
NM_000503.6 splice_region, splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00007833
2
Clinical Significance
Conservation
PhyloP100: 0.0750
Genes affected
EYA1 (HGNC:3519): (EYA transcriptional coactivator and phosphatase 1) This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may play a role in the developing kidney, branchial arches, eye, and ear. Mutations of this gene have been associated with branchiootorenal dysplasia syndrome, branchiootic syndrome, and sporadic cases of congenital cataracts and ocular anterior segment anomalies. A similar protein in mice can act as a transcriptional activator. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2013]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 8-71199428-A-G is Benign according to our data. Variant chr8-71199428-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194813.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=4}. Variant chr8-71199428-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000532 (81/152380) while in subpopulation SAS AF= 0.00145 (7/4830). AF 95% confidence interval is 0.000742. There are 0 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 81 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| EYA1 | NM_000503.6 | c.1699-8T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000340726.8 | |||
| LOC105375894 | XR_007060958.1 | n.206+83A>G | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| EYA1 | ENST00000340726.8 | c.1699-8T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000503.6 | P4 | |||
| ENST00000521685.5 | n.476+83A>G | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes 0.000525 AC: 80AN: 152262Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000802 AC: 197AN: 245564Hom.: 1 AF XY: 0.000790 AC XY: 105AN XY: 132942
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GnomAD4 exome AF: 0.000896 AC: 1305AN: 1456498Hom.: 2 Cov.: 31 AF XY: 0.000927 AC XY: 672AN XY: 724682
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GnomAD4 genome 0.000532 AC: 81AN: 152380Hom.: 0 Cov.: 33 AF XY: 0.000577 AC XY: 43AN XY: 74526
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 06, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 20, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | EYA1: BS1, BS2 - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 06, 2017 | c.1699-8T>C in intron 16 of EYA1: This variant is not expected to have clinical significance because a T>C change at this position does not diverge from the spl ice consensus sequence and is therefore unlikely to impact splicing. It has been identified in 0.2% (52/30260) of South Asian chromosomes by the Genome Aggregat ion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201537030). - |
Branchiootic syndrome 1 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Melnick-Fraser syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | - - |
Otofaciocervical syndrome 1 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
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