rs121909200

Positions:

chr8-71215630-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_000503.6(EYA1):c.1459T>C(p.Ser487Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S487L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EYA1
NM_000503.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 2.68

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 Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-71215629-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

PP5

Variant 8-71215630-A-G is Pathogenic according to our data. 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. Variant chr8-71215630-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA1	NM_000503.6 linkuse as main transcript	c.1459T>C	p.Ser487Pro	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.1459T>C	p.Ser487Pro	missense_variant	15/18	1	NM_000503.6	ENSP00000342626	P4	Q99502-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251282

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

EYA1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2024

The EYA1 c.1459T>C variant is predicted to result in the amino acid substitution p.Ser487Pro. This variant has been reported in many individuals with branchio-oto-renal syndrome (Reported as c.1360T>C, p.Ser454Pro in Abdelhak et al 1997. PubMed ID: 9361030; Buller C et al 2001. PubMed ID: 11734542; Mutsuddi M et al 2005. PubMed ID: 15802522; Heidet L et al 2017. PubMed ID: 28566479). Several different experimental studies suggest this variant impacts protein function (Buller C et al 2001. PubMed ID: 11734542; Mutsuddi M et al 2005. PubMed ID: 15802522; Rayapureddi JP et al 2006. PubMed ID: 16797546). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Melnick-Fraser syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 21, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects EYA1 function (PMID: 11734542, 15802522, 16797546, 24489909). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EYA1 protein function. ClinVar contains an entry for this variant (Variation ID: 7940). This variant is also known as S454P. This missense change has been observed in individuals with branchiootorenal syndrome (PMID: 8566479, 9361030, 10464653; Invitae). This variant is present in population databases (rs121909200, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 487 of the EYA1 protein (p.Ser487Pro). -

Branchiootorenal syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

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

Eigen

Benign

0.011

Eigen_PC

Benign

0.046

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.96

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

MetaSVM

Pathogenic

0.91

MutationAssessor

Benign

1.4

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

MutationTaster

Benign

1.0

A;A;A;A;A;A;A

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.8

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

REVEL

Pathogenic

0.72

Sift

Benign

0.091

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

Sift4G

Benign

0.091

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

Polyphen

0.21

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

Vest4

0.83

MutPred

0.90

Loss of stability (P = 0.1159);Loss of stability (P = 0.1159);Loss of stability (P = 0.1159);.;.;.;Loss of stability (P = 0.1159);Loss of stability (P = 0.1159);.;.;.;.;.;

MVP

0.92

MPC

0.39

ClinPred

0.77

GERP RS

3.3

Varity_R

0.60

gMVP

0.90

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