rs139717960

chr8-71215629-G-Achr8-71215629-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 4P and 11B. PM1 PM5 BP4_Moderate BP6 BS1 BS2

The NM_000503.6(EYA1):c.1460C>T(p.Ser487Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,036 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S487P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: EYA1 NM_000503.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 7.95

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 Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000503.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-71215630-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7940.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07379019).
• BP6: Variant 8-71215629-G-A is Benign according to our data. Variant chr8-71215629-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228678.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=2, Uncertain_significance=1}. Variant chr8-71215629-G-A is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000703 (107/152284) while in subpopulation NFE AF= 0.00138 (94/68026). AF 95% confidence interval is 0.00116. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 107 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA1	NM_000503.6	c.1460C>T	p.Ser487Leu	missense_variant	15/18	ENST00000340726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8	c.1460C>T	p.Ser487Leu	missense_variant	15/18	1	NM_000503.6	P4

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000776 AC: 195 AN: 251262 Hom.: 0 AF XY: 0.000832 AC XY: 113 AN XY: 135778

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00130 AC: 1897 AN: 1461752 Hom.: 2 Cov.: 32 AF XY: 0.00128 AC XY: 930 AN XY: 727186

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00158

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74470

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00126 Hom.: 0

Bravo AF: 0.000846

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000717 AC: 87

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00169

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2020	This variant is associated with the following publications: (PMID: 24429398, 18220287, 15146463, 22995991, 24123792, 26489027, 9361030, 29966037) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	EYA1: BS1, BS2 -

Otofaciocervical syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

EYA1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

The EYA1 c.1460C>T variant is predicted to result in the amino acid substitution p.Ser487Leu. This variant has been reported in at least one individual with branchiootorenal (BOR) syndrome (referred to as c.1361T>C, p.Ser454Leu, Chang et al. 2004. PubMed ID: 15146463) and another individual with progressive hearing loss (Table S13, Neveling et al. 2013. PubMed ID: 24123792). It has been interpreted as non-pathogenic for congenital anomalies of the kidney and urinary tract (CAKUT, Table S2, Hwang et al. 2014. PubMed ID: 24429398;) and uncertain significance for BOR syndrome (Table S5, Nicolaou et al. 2016. PubMed ID: 26489027). This variant has been reported 212 times among ~283,000 alleles (~0.08%) in a large population database (https://gnomad.broadinstitute.org/variant/chr8-72127864-G-A), and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/228678/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Branchiootic syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 12, 2019

The p.Ser487Leu variant in EYA1 is classified as likely benign because it is present in 0.13% (177/129002) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in 1 individual with Branchio-oto-renal syndrome, 2 individuals with hearing loss, and 4 individuals with vesicouretal reflux/CAKUT (Chang 2004, Neveling 2013, Hwang 2014, Nicolaou 2016). It has also been identified in 1 individual with ear abnormalities and hypoplastic kidneys who also had a 2q23 microdeletion and a de novo pathogenic variant in the CHD7 gene; the p.Ser487Leu variant segregated in the father with branchial cyst and duplication of renal collecting system (Badilla-Porras 2012). This variant has been reported by our laboratory in 2 unrelated Caucasian individuals with sensorineural hearing loss due to alternate genetic etiologies as well as in an unaffected parent. In summary, the frequency data and identification of this variant in individuals with an alternate genetic etiology and unaffected parent support a likely benign classification, despite the reports in the literature. ACMG/AMP Criteria applied: BA1, BS2_Supporting, BP5, PS4_Supporting. -

Melnick-Fraser syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 17, 2023

- -

Developmental cataract Benign:1

Benign, no assertion criteria provided

research

Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania

May 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;T;T;.;.;.;T;T;.;.;.;.;.
Eigen	Benign	0.084
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.074	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	-0.030	N;N;N;.;.;.;N;N;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.4	N;.;N;N;N;N;.;.;.;.;.;N;N
REVEL	Pathogenic	0.71
Sift	Benign	0.51	T;.;T;T;T;T;.;.;.;.;.;T;T
Sift4G	Benign	0.28	T;.;T;T;T;T;.;.;.;.;.;T;T
Polyphen		0.28	B;B;B;.;B;B;B;B;.;.;.;.;.
Vest4		0.64
MVP		0.81
MPC		0.22
ClinPred		0.056	T
GERP RS		4.4
Varity_R		0.22
gMVP		0.70

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

LitVar

Other links and lift over

dbSNP: rs139717960; hg19: chr8-72127864; COSMIC: COSV58169756;