rs121909196

Positions:

• chr8-71216733-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R440W) has been classified as Uncertain significance.

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

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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/exons	MANE	UniProt
EYA1	NM_000503.6	c.1319G>A	p.Arg440Gln	missense_variant	14/18	ENST00000340726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8	c.1319G>A	p.Arg440Gln	missense_variant	14/18	1	NM_000503.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Branchiootic syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Aug 02, 2022

- -

EYA1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

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

Pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Jan 17, 2019

- -

Melnick-Fraser syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

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). This variant is also known as c.1220G>A (p.Arg407Gln). ClinVar contains an entry for this variant (Variation ID: 7935). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Branchiootorenal syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1997

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 19, 2011

- -

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;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
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;