rs117149407

Positions:

• chr8-71199423-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000340726.8(EYA1):​c.1699-3C>T variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.0159 in 1,609,482 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 33)
  • Exomes 𝑓: 0.016 (252 hom.)
• Consequence: EYA1 ENST00000340726.8 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002517
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.84

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 8-71199423-G-A is Benign according to our data. Variant chr8-71199423-G-A is described in ClinVar as [Benign]. Clinvar id is 48105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-71199423-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0117 (1779/152352) while in subpopulation AMR AF= 0.0216 (331/15306). AF 95% confidence interval is 0.0197. There are 17 homozygotes in gnomad4. There are 848 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1779 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA1	NM_000503.6	c.1699-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000340726.8	NP_000494.2
LOC105375894	XR_007060958.1	n.206+78G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8	c.1699-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000503.6	ENSP00000342626	P4
	ENST00000521685.5	n.476+78G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1781 AN: 152234 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0151 AC: 3721 AN: 246102 Hom.: 51 AF XY: 0.0148 AC XY: 1974 AN XY: 133268

Gnomad AFR exome AF: 0.00323

Gnomad AMR exome AF: 0.0321

Gnomad ASJ exome AF: 0.00770

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.0172

Gnomad FIN exome AF: 0.00682

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0163 AC: 23811 AN: 1457130 Hom.: 252 Cov.: 31 AF XY: 0.0163 AC XY: 11791 AN XY: 724954

Gnomad4 AFR exome AF: 0.00260

Gnomad4 AMR exome AF: 0.0298

Gnomad4 ASJ exome AF: 0.00774

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0191

Gnomad4 FIN exome AF: 0.00818

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0117 AC: 1779 AN: 152352 Hom.: 17 Cov.: 33 AF XY: 0.0114 AC XY: 848 AN XY: 74504

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.0216

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0128 Hom.: 3

Bravo AF: 0.0132

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0156

EpiControl AF: 0.0141

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2012	1699-3C>T in Intron 16 of EYA1: This variant is not expected to have clinical si gnificance because it has been identified in 1.6% (114/7020) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs117149407). -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

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	-0.47
CADD	Benign	12
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.070		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: rs117149407; hg19: chr8-72111658;