chr8-71216734-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM5PP3_ModerateBS2

The NM_000503.6(EYA1):c.1318C>T(p.Arg440Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000164 in 1,461,824 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R440Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

EYA1
NM_000503.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.64

Publications

1 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:

ENSG00000285579 (HGNC:):

ENSG00000285579 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-71216733-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

BS2

High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA1	NM_000503.6 link	c.1318C>T	p.Arg440Trp	missense_variant	Exon 14 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.1318C>T	p.Arg440Trp	missense_variant	Exon 14 of 18	1	NM_000503.6	ENSP00000342626.3		Q99502-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251348

AF XY:

0.0000294

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 FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111968

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 05, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg440Trp variant in EYA1 has not been previously reported in individuals with hearing lo ss or Branchio-oto-renal syndrome (BOR), but has been identified in 2/8600 Europ ean American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS/; dbSNP rs376931849). Although this variant has been seen in th e general population, its frequency is not high enough to rule out a pathogenic role. A different variant at this same position, p.Arg440Gln, is pathogenic for Branchio-oto-renal syndrome, suggesting that variants at this position may not b e tolerated. Computational prediction tools and conservation analysis suggest th at the p.Arg440Trp variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg440Trp va riant is uncertain. -

Branchiootic syndrome 1;C3714941:Otofaciocervical syndrome 1;C4551702:Branchiootorenal syndrome 1

Uncertain:1

Apr 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

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

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.90

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

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.9

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

PhyloP100

4.6

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.5

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

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.93

MVP

0.93

MPC

0.83

ClinPred

0.95

GERP RS

4.5

Varity_R

0.67

gMVP

0.83

Mutation Taster

=41/59

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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chr8-71216734-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over