rs121909196

Variant names:

• chr8-71216733-C-T
• rs121909196
• NM_000503.6:c.1319G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000503.6(EYA1):​c.1319G>A​(p.Arg440Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EYA1 NM_000503.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.86

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]

ENSG00000285579 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 8-71216733-C-T is Pathogenic according to our data. 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. Variant chr8-71216733-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA1	NM_000503.6	c.1319G>A	p.Arg440Gln	missense_variant	Exon 14 of 18	ENST00000340726.8	NP_000494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8	c.1319G>A	p.Arg440Gln	missense_variant	Exon 14 of 18	1	NM_000503.6	ENSP00000342626.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Branchiootorenal syndrome 1 Pathogenic:2

Jan 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 08, 2024

Center for Statistical Genetics, Columbia University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Branchiootic syndrome 1 Pathogenic:1

Aug 02, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

EYA1-related disorder Pathogenic:1

Sep 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The EYA1 c.1319G>A variant is predicted to result in the amino acid substitution p.Arg440Gln. This variant is also referred to as c.1220G>A or R407Q in the literature, corresponding to NM_172060. It has been reported in individuals with branchio-oto-renal syndrome (see, for example, Kumar et al. 1997. PubMed ID: 10464653; Orten et al. 2008. PubMed ID: 18220287; Mann et al. 2019. PubMed ID: 30655312), including some in whom it was reported de novo (Masuda et al. 2022. PubMed ID: 35046468; Cho et al. 2024. PubMed ID: 39125727). An in vivo experimental study indicated this variant affected development of the otic vesicle and vestibulocochlear nerve in Xenopus laevis embryos (referred to as R435Q, Li et al. 2010. PubMed ID: 19951260). An additional study indicated this variant protein was able to translocate into the nucleus with similar efficiency to wild type (Musharraf et al. 2014. PubMed ID: 24489909). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Branchiooculofacial syndrome Pathogenic:1

Jan 17, 2019

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Melnick-Fraser syndrome Pathogenic:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 440 of the EYA1 protein (p.Arg440Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with branchiootorenal syndrome (PMID: 10464653, 15146463, 18220287, 21280147, 28832562). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this EYA1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 10,567 individuals referred to our laboratory for EYA1 testing. This variant is also known as c.1220G>A (p.Arg407Gln). ClinVar contains an entry for this variant (Variation ID: 7935). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt EYA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects EYA1 function (PMID: 19951260, 24489909). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Rare genetic deafness Pathogenic:1

May 19, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2+PS4+PP1_Strong+PM1+PS3_Moderate+PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;D;D;.;.;.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;.;.;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.9	M;M;M;.;.;.;M;M;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.7	D;.;D;D;D;D;.;.;.;.;.;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0070	D;.;D;D;D;D;.;.;.;.;.;D;D
Sift4G	Uncertain	0.010	D;.;D;D;D;D;.;.;.;.;.;D;D
Polyphen		1.0	D;D;D;.;D;D;D;D;.;.;.;.;.
Vest4		0.92
MutPred		0.89		Loss of MoRF binding (P = 0.0666);Loss of MoRF binding (P = 0.0666);Loss of MoRF binding (P = 0.0666);.;.;.;Loss of MoRF binding (P = 0.0666);Loss of MoRF binding (P = 0.0666);.;.;.;.;.;
MVP		0.95
MPC		0.73
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.53
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: -1
DS_DL_spliceai		0.59		Position offset: -41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909196; hg19: chr8-72128968;