rs77825059

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000503.6(EYA1):c.782C>T(p.Pro261Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,614,064 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P261P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00092 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00062 ( 10 hom. )

Consequence

EYA1
NM_000503.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 9.52

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009139895).

BP6

Variant 8-71299091-G-A is Benign according to our data. Variant chr8-71299091-G-A is described in ClinVar as [Benign]. Clinvar id is 363655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-71299091-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000919 (140/152260) while in subpopulation EAS AF= 0.0231 (119/5160). AF 95% confidence interval is 0.0197. There are 2 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 140 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA1	NM_000503.6 linkuse as main transcript	c.782C>T	p.Pro261Leu	missense_variant	9/18	ENST00000340726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8 linkuse as main transcript	c.782C>T	p.Pro261Leu	missense_variant	9/18	1	NM_000503.6	P4	Q99502-1

Frequencies

GnomAD3 genomes

AF:

0.000920

AC:

140

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.0230

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00212

AC:

534

AN:

251472

Hom.:

AF XY:

0.00192

AC XY:

261

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00357

Gnomad EAS exome

AF:

0.0258

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000439

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000616

AC:

900

AN:

1461804

Hom.:

Cov.:

AF XY:

0.000586

AC XY:

426

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00295

Gnomad4 EAS exome

AF:

0.0173

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.000927

GnomAD4 genome

AF:

0.000919

AC:

140

AN:

152260

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.0231

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000981

Hom.:

Bravo

AF:

0.00105

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00213

AC:

258

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro261Leu in Exon 08 of EYA1: This variant is not expected to have clinical sign ificance because it has been identified in 5.8% (7/120) of chromosomes from a po pulation in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs7782 5059). -

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

Invitae

Jan 26, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2019

This variant is associated with the following publications: (PMID: 24429398) -

Otofaciocervical syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

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

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

MetaRNN

Benign

0.0091

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

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

0.83

L;L;L;.;.;.;L;L;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.6

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

REVEL

Uncertain

0.49

Sift

Benign

0.20

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

Sift4G

Benign

0.35

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

Polyphen

1.0

D;D;D;.;B;D;D;D;.;.;.;.;.

Vest4

0.74

MVP

0.80

MPC

0.84

ClinPred

0.050

GERP RS

5.2

Varity_R

0.21

gMVP

0.65

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