rs139717960

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 4P and 11B. PM1PM5BP4_ModerateBP6BS1BS2

The ENST00000340726.8(EYA1):c.1460C>T(p.Ser487Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,036 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S487P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 2 hom. )

Consequence

EYA1
ENST00000340726.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 7.95

Variant links:

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]

EYA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000340726.8

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-71215630-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7940.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.07379019).

BP6

Variant 8-71215629-G-A is Benign according to our data. Variant chr8-71215629-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228678.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=6, Uncertain_significance=1}. Variant chr8-71215629-G-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000703 (107/152284) while in subpopulation NFE AF= 0.00138 (94/68026). AF 95% confidence interval is 0.00116. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 107 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA1	NM_000503.6 linkuse as main transcript	c.1460C>T	p.Ser487Leu	missense_variant	15/18	ENST00000340726.8	NP_000494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8 linkuse as main transcript	c.1460C>T	p.Ser487Leu	missense_variant	15/18	1	NM_000503.6	ENSP00000342626	P4	Q99502-1

Frequencies

GnomAD3 genomes

AF:

0.000703

AC:

107

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000776

AC:

195

AN:

251262

Hom.:

AF XY:

0.000832

AC XY:

113

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00142

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00130

AC:

1897

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

930

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.00158

Gnomad4 OTH exome

AF:

0.00128

GnomAD4 genome

AF:

0.000703

AC:

107

AN:

152284

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00138

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.000846

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000717

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00169

EpiControl

AF:

0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2020	This variant is associated with the following publications: (PMID: 24429398, 18220287, 15146463, 22995991, 24123792, 26489027, 9361030, 29966037) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	EYA1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 02, 2017	- -

Otofaciocervical syndrome 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

EYA1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

The EYA1 c.1460C>T variant is predicted to result in the amino acid substitution p.Ser487Leu. This variant has been reported in at least one individual with branchiootorenal (BOR) syndrome (referred to as c.1361T>C, p.Ser454Leu, Chang et al. 2004. PubMed ID: 15146463) and another individual with progressive hearing loss (Table S13, Neveling et al. 2013. PubMed ID: 24123792). It has been interpreted as non-pathogenic for congenital anomalies of the kidney and urinary tract (CAKUT, Table S2, Hwang et al. 2014. PubMed ID: 24429398;) and uncertain significance for BOR syndrome (Table S5, Nicolaou et al. 2016. PubMed ID: 26489027). This variant has been reported 212 times among ~283,000 alleles (~0.08%) in a large population database (https://gnomad.broadinstitute.org/variant/chr8-72127864-G-A), and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/228678/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Branchiootic syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 12, 2019

The p.Ser487Leu variant in EYA1 is classified as likely benign because it is present in 0.13% (177/129002) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in 1 individual with Branchio-oto-renal syndrome, 2 individuals with hearing loss, and 4 individuals with vesicouretal reflux/CAKUT (Chang 2004, Neveling 2013, Hwang 2014, Nicolaou 2016). It has also been identified in 1 individual with ear abnormalities and hypoplastic kidneys who also had a 2q23 microdeletion and a de novo pathogenic variant in the CHD7 gene; the p.Ser487Leu variant segregated in the father with branchial cyst and duplication of renal collecting system (Badilla-Porras 2012). This variant has been reported by our laboratory in 2 unrelated Caucasian individuals with sensorineural hearing loss due to alternate genetic etiologies as well as in an unaffected parent. In summary, the frequency data and identification of this variant in individuals with an alternate genetic etiology and unaffected parent support a likely benign classification, despite the reports in the literature. ACMG/AMP Criteria applied: BA1, BS2_Supporting, BP5, PS4_Supporting. -

Melnick-Fraser syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2023

- -

Developmental cataract

Benign:1

Benign, no assertion criteria provided

research

Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania

May 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;T;T;.;.;.;T;T;.;.;.;.;.

Eigen

Benign

0.084

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;.;.;D;D;D;.;D;D;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.074

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

-0.030

N;N;N;.;.;.;N;N;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.4

N;.;N;N;N;N;.;.;.;.;.;N;N

REVEL

Pathogenic

0.71

Sift

Benign

0.51

T;.;T;T;T;T;.;.;.;.;.;T;T

Sift4G

Benign

0.28

T;.;T;T;T;T;.;.;.;.;.;T;T

Polyphen

0.28

B;B;B;.;B;B;B;B;.;.;.;.;.

Vest4

0.64

MVP

0.81

MPC

0.22

ClinPred

0.056

GERP RS

4.4

Varity_R

0.22

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over