rs1445398

Positions:

• chr8-71299060-T-C

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.813A>G​(p.Thr271=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0998 in 1,613,700 control chromosomes in the GnomAD database, including 11,653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (1078 hom., cov: 33)
  • Exomes 𝑓: 0.10 (10575 hom.)
• Consequence: EYA1 NM_000503.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.224

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=-0.65).
• BP6: Variant 8-71299060-T-C is Benign according to our data. Variant chr8-71299060-T-C is described in ClinVar as [Benign]. Clinvar id is 48109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-71299060-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.224 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA1	NM_000503.6	c.813A>G	p.Thr271=	synonymous_variant	9/18	ENST00000340726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8	c.813A>G	p.Thr271=	synonymous_variant	9/18	1	NM_000503.6	P4

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 13906 AN: 152120 Hom.: 1078 Cov.: 33

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0646

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0849

Gnomad OTH AF: 0.0841

GnomAD3 exomes AF: 0.130 AC: 32752 AN: 251456 Hom.: 3629 AF XY: 0.122 AC XY: 16588 AN XY: 135904

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.0655

Gnomad EAS exome AF: 0.432

Gnomad SAS exome AF: 0.0935

Gnomad FIN exome AF: 0.0688

Gnomad NFE exome AF: 0.0839

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.101 AC: 147121 AN: 1461462 Hom.: 10575 Cov.: 32 AF XY: 0.0993 AC XY: 72166 AN XY: 727068

Gnomad4 AFR exome AF: 0.0367

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.0654

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.0945

Gnomad4 FIN exome AF: 0.0761

Gnomad4 NFE exome AF: 0.0878

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0914 AC: 13916 AN: 152238 Hom.: 1078 Cov.: 33 AF XY: 0.0939 AC XY: 6988 AN XY: 74432

Gnomad4 AFR AF: 0.0386

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.0573

Gnomad4 EAS AF: 0.436

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0646

Gnomad4 NFE AF: 0.0848

Gnomad4 OTH AF: 0.0847

Alfa AF: 0.0901 Hom.: 1605

Bravo AF: 0.103

Asia WGS AF: 0.250 AC: 867 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Branchiootic syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2011	The Thr271Thr variant has been reported in dbSNP in over ten populations with mi nor allele frequencies as high as 53% (rs1445398). In addition, the variant does not result in an amino acid substitution nor is it predicted to impact splicing . Therfore, this variant is highly likely to be benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Otofaciocervical syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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

- -

Branchiootorenal syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.3
DANN	Benign	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: rs1445398; hg19: chr8-72211295; COSMIC: COSV58172026;