NM_000503.6:c.813A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000503.6(EYA1):c.813A>G(p.Thr271Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0998 in 1,613,700 control chromosomes in the GnomAD database, including 11,653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.091 ( 1078 hom., cov: 33)

Exomes 𝑓: 0.10 ( 10575 hom. )

Consequence

EYA1
NM_000503.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.224

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

branchio-oto-renal syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
branchiootorenal syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
branchiootic syndrome 1
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
branchiootic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EYA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 8-71299060-T-C is Benign according to our data. Variant chr8-71299060-T-C is described in ClinVar as Benign. ClinVar VariationId is 48109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.224 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA1	NM_000503.6 link	c.813A>G	p.Thr271Thr	synonymous_variant	Exon 9 of 18	ENST00000340726.8	NP_000494.2	Q99502-1A0A024R813B3KXR1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8 link	c.813A>G	p.Thr271Thr	synonymous_variant	Exon 9 of 18	1	NM_000503.6	ENSP00000342626.3		Q99502-1

Frequencies

GnomAD3 genomes

AF:

0.0914

AC:

13906

AN:

152120

Hom.:

1078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0387

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.176

Gnomad ASJ

AF:

0.0573

Gnomad EAS

AF:

0.436

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.0646

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0849

Gnomad OTH

AF:

0.0841

GnomAD2 exomes

AF:

0.130

AC:

32752

AN:

251456

AF XY:

0.122

show subpopulations

Gnomad AFR exome

AF:

0.0348

Gnomad AMR exome

AF:

0.260

Gnomad ASJ exome

AF:

0.0655

Gnomad EAS exome

AF:

0.432

Gnomad FIN exome

AF:

0.0688

Gnomad NFE exome

AF:

0.0839

Gnomad OTH exome

AF:

0.113

GnomAD4 exome

AF:

0.101

AC:

147121

AN:

1461462

Hom.:

10575

Cov.:

AF XY:

0.0993

AC XY:

72166

AN XY:

727068

show subpopulations

African (AFR)

AF:

0.0367

AC:

1229

AN:

33478

American (AMR)

AF:

0.250

AC:

11186

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0654

AC:

1709

AN:

26132

East Asian (EAS)

AF:

0.417

AC:

16543

AN:

39688

South Asian (SAS)

AF:

0.0945

AC:

8151

AN:

86254

European-Finnish (FIN)

AF:

0.0761

AC:

4064

AN:

53420

Middle Eastern (MID)

AF:

0.0496

AC:

286

AN:

5768

European-Non Finnish (NFE)

AF:

0.0878

AC:

97570

AN:

1111630

Other (OTH)

AF:

0.106

AC:

6383

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

6537

13075

19612

26150

32687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3878

7756

11634

15512

19390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0914

AC:

13916

AN:

152238

Hom.:

1078

Cov.:

AF XY:

0.0939

AC XY:

6988

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0386

AC:

1603

AN:

41560

American (AMR)

AF:

0.177

AC:

2706

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

199

AN:

3470

East Asian (EAS)

AF:

0.436

AC:

2243

AN:

5144

South Asian (SAS)

AF:

0.106

AC:

513

AN:

4822

European-Finnish (FIN)

AF:

0.0646

AC:

685

AN:

10604

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0848

AC:

5771

AN:

68020

Other (OTH)

AF:

0.0847

AC:

179

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

594

1188

1781

2375

2969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0908

Hom.:

2773

Bravo

AF:

0.103

Asia WGS

AF:

0.250

AC:

867

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Branchiootic syndrome 1

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Thr271Thr variant has been reported in dbSNP in over ten populations with mi nor allele frequencies as high as 53% (rs1445398). In addition, the variant does not result in an amino acid substitution nor is it predicted to impact splicing . Therfore, this variant is highly likely to be benign. -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Otofaciocervical syndrome 1

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Melnick-Fraser syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Branchiootorenal syndrome 1

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

4.3

(source)

DANN

Benign

0.70

PhyloP100

-0.22

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over