rs121909199

Positions:

chr8-71216776-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BS1BS2

The NM_000503.6(EYA1):c.1276G>A(p.Gly426Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,614,130 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G426G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

EYA1
NM_000503.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:3

Conservation

PhyloP100: 7.86

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:

EYA1 (HGNC:):

EYA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.805

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000263 (4/152284) while in subpopulation EAS AF= 0.00058 (3/5172). AF 95% confidence interval is 0.000157. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA1	NM_000503.6 linkuse as main transcript	c.1276G>A	p.Gly426Ser	missense_variant	14/18	ENST00000340726.8	NP_000494.2	Q99502-1A0A024R813B3KXR1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8 linkuse as main transcript	c.1276G>A	p.Gly426Ser	missense_variant	14/18	1	NM_000503.6	ENSP00000342626.3		Q99502-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251308

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00190

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000424

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00144

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000192

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000140

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Branchiootorenal syndrome with cataract

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 12, 2000

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 25, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gly426Ser (c.1276G>A) variant in EYA1 has been reported in one Japanese individual with c onductive hearing loss with additional clinical features of branchio-oto-renal s yndrome (Azuma 2000), and parental testing confirmed de novo occurrence of the v ariant in the individual. This variant has also been identified in 0.18% (33/188 60) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs121909199); however this frequency is not hi gh enough to rule out a pathogenic role. The variant is also listed in ClinVar ( Variant ID 22977). Computational prediction tools and conservation analysis sugg est the variant may impact the protein. However, several in vitro functional stu dies provide conflicting data on the impact of the variant to normal protein fun ction (Buller 2001, Mutsuddi 2005, Rayapureddi 2006, Zou 2008, Li 2010, Ahmed 20 12, Patrick 2013, Musharraf 2014). It should be noted that in vitro studies may not accurately reflect biological function. In summary, while there is some sus picion for a pathogenic role, the clinical significance of the p.Gly426Ser varia nt is uncertain. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2024

The c.1276G>A (p.G426S) alteration is located in exon 14 (coding exon 12) of the EYA1 gene. This alteration results from a G to A substitution at nucleotide position 1276, causing the glycine (G) at amino acid position 426 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2024

Functional studies for this variant disagree on its effect; some indicate G426S or equivalent homologs reduce transcription level, affect optic development, and reduce interaction with Sox2, while others indicate G426S does not differ from wild-type (PMID: 15802522, 19951260, 18678597, 11950062, 24489909); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29043394, 16797546, 11734542, 23435380, 22340499, 24752894, 18678597, 19951260, 11950062, 24489909, 15802522, 35114279, 30221713, 38224868, 34868248, 34515852, 37479820, 37167448, 39125727, 10655545) -

Branchiootic syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Branchiootorenal syndrome 1

Benign:1

Benign, no assertion criteria provided

clinical testing

Pediatric Nephrology (Iijima Lab), Kobe University Graduate School of Medicine

Jul 27, 2017

Two cases without BOR syndrome possessed this variant. We conclude this is benign. -

Otofaciocervical syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

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

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.80

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

MetaSVM

Uncertain

0.55

MutationAssessor

Pathogenic

3.1

M;M;M;.;.;.;M;M;.;.;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.6

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

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0080

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

Polyphen

0.89

P;P;P;.;P;P;P;P;.;.;.;.;.

Vest4

0.96

MutPred

0.90

Gain of glycosylation at G426 (P = 0.062);Gain of glycosylation at G426 (P = 0.062);Gain of glycosylation at G426 (P = 0.062);.;.;.;Gain of glycosylation at G426 (P = 0.062);Gain of glycosylation at G426 (P = 0.062);.;.;.;.;.;

MVP

0.97

MPC

0.59

ClinPred

0.93

GERP RS

5.4

Varity_R

0.81

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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