rs1554541834

Positions:

• chr8-71299174-TGAGCTGTTATAATACTGTGCGTACTGACCCTGGCCAAAACTGGGATAAGACGGATAGTCCTACCAAATCAAACC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000503.6(EYA1):​c.640-15_698del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EYA1 NM_000503.6 splice_acceptor, coding_sequence, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.61

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-71299174-TGAGCTGTTATAATACTGTGCGTACTGACCCTGGCCAAAACTGGGATAAGACGGATAGTCCTACCAAATCAAACC-T is Pathogenic according to our data. Variant chr8-71299174-TGAGCTGTTATAATACTGTGCGTACTGACCCTGGCCAAAACTGGGATAAGACGGATAGTCCTACCAAATCAAACC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 459256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA1	NM_000503.6	c.640-15_698del		splice_acceptor_variant, coding_sequence_variant, intron_variant	9/18	ENST00000340726.8	NP_000494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8	c.640-15_698del		splice_acceptor_variant, coding_sequence_variant, intron_variant	9/18	1	NM_000503.6	ENSP00000342626	P4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melnick-Fraser syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 14, 2022

This variant results in the deletion of the intron 8 - exon 9 junction (c.640-15_698del) of the EYA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EYA1 are known to be pathogenic (PMID: 10464653, 18220287). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with EYA1-related conditions (PMID: 12404110; Invitae). This variant is also known as a deletion starting in intron 6 and extending into exon 7. ClinVar contains an entry for this variant (Variation ID: 459256). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 01, 2022

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8092198, 1478663, 12404110) -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554541834; hg19: chr8-72211409;