rs10103397

Positions:

• chr8-71199364-A-G
• chr8-71199364-A-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.1755T>C​(p.His585=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 1,610,680 control chromosomes in the GnomAD database, including 100,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10508 hom., cov: 32)
  • Exomes 𝑓: 0.34 (90491 hom.)
• Consequence: EYA1 NM_000503.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.426

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 8-71199364-A-G is Benign according to our data. Variant chr8-71199364-A-G is described in ClinVar as [Benign]. Clinvar id is 48107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-71199364-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.426 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA1	NM_000503.6	c.1755T>C	p.His585=	synonymous_variant	18/18	ENST00000340726.8	NP_000494.2
LOC105375894	XR_007060958.1	n.206+19A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8	c.1755T>C	p.His585=	synonymous_variant	18/18	1	NM_000503.6	ENSP00000342626	P4
	ENST00000521685.5	n.476+19A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54678 AN: 151900 Hom.: 10476 Cov.: 32

Gnomad AFR AF: 0.354

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.360

GnomAD3 exomes AF: 0.396 AC: 98291 AN: 248410 Hom.: 21910 AF XY: 0.389 AC XY: 52282 AN XY: 134340

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.523

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.780

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.345

Gnomad NFE exome AF: 0.299

Gnomad OTH exome AF: 0.358

GnomAD4 exome AF: 0.339 AC: 493791 AN: 1458662 Hom.: 90491 Cov.: 32 AF XY: 0.340 AC XY: 246908 AN XY: 725630

Gnomad4 AFR exome AF: 0.352

Gnomad4 AMR exome AF: 0.513

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.784

Gnomad4 SAS exome AF: 0.449

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.305

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.360 AC: 54766 AN: 152018 Hom.: 10508 Cov.: 32 AF XY: 0.368 AC XY: 27327 AN XY: 74320

Gnomad4 AFR AF: 0.354

Gnomad4 AMR AF: 0.439

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.778

Gnomad4 SAS AF: 0.484

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.303

Gnomad4 OTH AF: 0.368

Alfa AF: 0.315 Hom.: 2591

Bravo AF: 0.366

Asia WGS AF: 0.637 AC: 2215 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 28, 2010	The His585His variant is a common benign variant present in ~40% of the African population, ~75% of the Asian population, ~20% of the Caucasian population (dbSN P - rs10103397). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Branchiootic syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Otofaciocervical syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Melnick-Fraser syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

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	-0.88
CADD	Benign	0.14
DANN	Benign	0.50

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: rs10103397; hg19: chr8-72111599; COSMIC: COSV100378647;