rs4738118

chr8-71216774-G-Achr8-71216774-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000503.6(EYA1):c.1278C>T(p.Gly426=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,682 control chromosomes in the GnomAD database, including 28,388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. GG426GG?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.15 (2843 hom., cov: 32)
  • Exomes 𝑓: 0.15 (25545 hom.)
• Consequence: EYA1 NM_000503.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.136

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-71216774-G-A is Benign according to our data. Variant chr8-71216774-G-A is described in ClinVar as [Benign]. Clinvar id is 48101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-71216774-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.136 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA1	NM_000503.6	c.1278C>T	p.Gly426=	synonymous_variant	14/18	ENST00000340726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8	c.1278C>T	p.Gly426=	synonymous_variant	14/18	1	NM_000503.6	P4

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23031 AN: 151934 Hom.: 2833 Cov.: 32

Gnomad AFR AF: 0.0921

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.149

GnomAD3 exomes AF: 0.219 AC: 54973 AN: 251276 Hom.: 9606 AF XY: 0.215 AC XY: 29190 AN XY: 135800

Gnomad AFR exome AF: 0.0902

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.668

Gnomad SAS exome AF: 0.321

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.149 AC: 218212 AN: 1461630 Hom.: 25545 Cov.: 33 AF XY: 0.153 AC XY: 110966 AN XY: 727138

Gnomad4 AFR exome AF: 0.0875

Gnomad4 AMR exome AF: 0.342

Gnomad4 ASJ exome AF: 0.146

Gnomad4 EAS exome AF: 0.670

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.152 AC: 23074 AN: 152052 Hom.: 2843 Cov.: 32 AF XY: 0.161 AC XY: 11981 AN XY: 74318

Gnomad4 AFR AF: 0.0922

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.656

Gnomad4 SAS AF: 0.355

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.157

Alfa AF: 0.123 Hom.: 2210

Bravo AF: 0.155

Asia WGS AF: 0.513 AC: 1781 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2010	The Gly426Gly variant in EYA1 is a silent common benign variant present in ~10% of Caucasian and African populations, and in >50% of Asian populations (dbSNP- r s4738118). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Branchiootic syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Melnick-Fraser syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Otofaciocervical syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	3.0
Dann	Benign	0.54

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: rs4738118; hg19: chr8-72129009; COSMIC: COSV58162944;