Genetic Variant EYA1:p.Pro261Leu (chr8-71299091-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

7 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 363655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 140 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.782C>T	p.Pro261Leu	missense	Exon 9 of 18	NP_000494.2
EYA1	NM_001370333.1		c.869C>T	p.Pro290Leu	missense	Exon 10 of 19	NP_001357262.1	A0A2R8Y6K4
EYA1	NM_001370334.1		c.782C>T	p.Pro261Leu	missense	Exon 11 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.782C>T	p.Pro261Leu	missense	Exon 9 of 18	ENSP00000342626.3	Q99502-1
EYA1	ENST00000388742.8	TSL:1	c.782C>T	p.Pro261Leu	missense	Exon 8 of 17	ENSP00000373394.4	Q99502-1
EYA1	ENST00000419131.6	TSL:1	c.767C>T	p.Pro256Leu	missense	Exon 8 of 16	ENSP00000410176.1	Q99502-3

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

GnomAD2 exomes

AF:

0.00212

AC:

534

AN:

251472

AF XY:

0.00192

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 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

African (AFR)

AF:

0.0000896

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00295

AC:

AN:

26132

East Asian (EAS)

AF:

0.0173

AC:

685

AN:

39692

South Asian (SAS)

AF:

0.000278

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000468

AC:

AN:

1111956

Other (OTH)

AF:

0.000927

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000919

AC:

140

AN:

152260

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41558

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.0231

AC:

119

AN:

5160

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68018

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000775

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Branchiootic syndrome 1 (1)

Melnick-Fraser syndrome (1)

not provided (1)

Otofaciocervical syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0091

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

0.83

PhyloP100

9.5

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.49

Sift

Benign

0.20

Sift4G

Benign

0.35

Polyphen

1.0

Vest4

0.74

MVP

0.80

MPC

0.84

ClinPred

0.050

GERP RS

5.2

Varity_R

0.21

gMVP

0.65

Mutation Taster

=94/6

polymorphism

(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