Genetic Variant EYA1:p.His585Gln (chr8-71199364-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000503.6(EYA1):c.1755T>A(p.His585Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H585H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

EYA1
NM_000503.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.426

Publications

28 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:

ENSG00000254031 (HGNC:):

ENSG00000254031 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29870582).

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.1755T>A	p.His585Gln	missense	Exon 18 of 18	NP_000494.2
EYA1	NM_001370333.1		c.1842T>A	p.His614Gln	missense	Exon 19 of 19	NP_001357262.1	A0A2R8Y6K4
EYA1	NM_001370334.1		c.1755T>A	p.His585Gln	missense	Exon 20 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.1755T>A	p.His585Gln	missense	Exon 18 of 18	ENSP00000342626.3	Q99502-1
EYA1	ENST00000388742.8	TSL:1	c.1755T>A	p.His585Gln	missense	Exon 17 of 17	ENSP00000373394.4	Q99502-1
EYA1	ENST00000419131.6	TSL:1	c.1650T>A	p.His550Gln	missense	Exon 16 of 16	ENSP00000410176.1	Q99502-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

2628

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.0063

BayesDel_noAF

Benign

-0.25

CADD

Benign

8.8

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.34

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.10

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.30

MetaSVM

Uncertain

0.026

MutationAssessor

Benign

0.84

PhyloP100

-0.43

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.39

Sift

Benign

0.93

Sift4G

Benign

0.77

Polyphen

1.0

Vest4

0.48

MutPred

0.24

Loss of catalytic residue at L587 (P = 0.0944)

MVP

0.66

MPC

0.83

ClinPred

0.51

GERP RS

-12

Varity_R

0.15

gMVP

0.68

Mutation Taster

=63/37

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over