Genetic Variant EYA1:p.Ser487Leu (chr8-71215629-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 4P and 11B. PM1PM5BP4_ModerateBP6BS1BS2

The NM_000503.6(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
NM_000503.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.95

Publications

14 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: Orphanet, ClinGen
branchiootorenal syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
branchiootic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EYA1 links:

ENSG00000285579 (HGNC:):

ENSG00000285579 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000503.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-71215630-A-G is described in ClinVar as Pathogenic. ClinVar VariationId 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 VariationId is 228678.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 107 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000503.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EYA1	NM_000503.6	MANE Select	c.1460C>T	p.Ser487Leu	missense	Exon 15 of 18	NP_000494.2
EYA1	NM_001370333.1		c.1547C>T	p.Ser516Leu	missense	Exon 16 of 19	NP_001357262.1	A0A2R8Y6K4
EYA1	NM_001370334.1		c.1460C>T	p.Ser487Leu	missense	Exon 17 of 20	NP_001357263.1	Q99502-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EYA1	ENST00000340726.8	TSL:1 MANE Select	c.1460C>T	p.Ser487Leu	missense	Exon 15 of 18	ENSP00000342626.3	Q99502-1
EYA1	ENST00000388742.8	TSL:1	c.1460C>T	p.Ser487Leu	missense	Exon 14 of 17	ENSP00000373394.4	Q99502-1
EYA1	ENST00000419131.6	TSL:1	c.1355C>T	p.Ser452Leu	missense	Exon 13 of 16	ENSP00000410176.1	Q99502-3

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

GnomAD2 exomes

AF:

0.000776

AC:

195

AN:

251262

AF XY:

0.000832

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 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

African (AFR)

AF:

0.000209

AC:

AN:

33476

American (AMR)

AF:

0.000805

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00158

AC:

1759

AN:

1111890

Other (OTH)

AF:

0.00128

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

197

296

394

493

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.000703

AC:

107

AN:

152284

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41560

American (AMR)

AF:

0.000327

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00121

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Otofaciocervical syndrome 1 (2)

Branchiootic syndrome 1 (1)

Developmental cataract (1)

EYA1-related disorder (1)

Melnick-Fraser syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

Eigen

Benign

0.084

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.074

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

-0.030

PhyloP100

8.0

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.4

REVEL

Pathogenic

0.71

Sift

Benign

0.51

Sift4G

Benign

0.28

Polyphen

0.28

Vest4

0.64

MVP

0.81

MPC

0.22

ClinPred

0.056

GERP RS

4.4

Varity_R

0.22

gMVP

0.70

Mutation Taster

=0/100

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over