6-133528730-C-T

Position:

• chr6-133528730-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000355286.12(EYA4):​c.1845C>T​(p.Asn615=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0124 in 1,611,356 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (15 hom., cov: 32)
  • Exomes 𝑓: 0.013 (186 hom.)
• Consequence: EYA4 ENST00000355286.12 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 5.01

Genes affected

EYA4 (HGNC:3522): (EYA transcriptional coactivator and phosphatase 4) This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may act as a transcriptional activator through its protein phosphatase activity, and it may be important for eye development, and for continued function of the mature organ of Corti. Mutations in this gene are associated with postlingual, progressive, autosomal dominant hearing loss at the deafness, autosomal dominant non-syndromic sensorineural 10 locus. The encoded protein is also a putative oncogene that mediates DNA repair, apoptosis, and innate immunity following DNA damage, cellular damage, and viral attack. Defects in this gene are also associated with dilated cardiomyopathy 1J. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

TARID (HGNC:50506): (TCF21 antisense RNA inducing promoter demethylation)

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 6-133528730-C-T is Benign according to our data. Variant chr6-133528730-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 36031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-133528730-C-T is described in Lovd as [Likely_benign]. Variant chr6-133528730-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00898 (1367/152254) while in subpopulation SAS AF= 0.0213 (103/4826). AF 95% confidence interval is 0.018. There are 15 homozygotes in gnomad4. There are 633 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1367 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA4	NM_004100.5	c.1845C>T	p.Asn615=	synonymous_variant	20/20	ENST00000355286.12	NP_004091.3
TARID	NR_109982.1	n.2285+7050G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12	c.1845C>T	p.Asn615=	synonymous_variant	20/20	1	NM_004100.5	ENSP00000347434	P4
TARID	ENST00000607033.5	n.2261+7050G>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00899 AC: 1367 AN: 152136 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.0117 AC: 2935 AN: 251228 Hom.: 43 AF XY: 0.0127 AC XY: 1730 AN XY: 135764

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.0414

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0258

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0127 AC: 18598 AN: 1459102 Hom.: 186 Cov.: 31 AF XY: 0.0133 AC XY: 9636 AN XY: 726066

Gnomad4 AFR exome AF: 0.00216

Gnomad4 AMR exome AF: 0.00434

Gnomad4 ASJ exome AF: 0.0422

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0249

Gnomad4 FIN exome AF: 0.00391

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0141

GnomAD4 genome AF: 0.00898 AC: 1367 AN: 152254 Hom.: 15 Cov.: 32 AF XY: 0.00850 AC XY: 633 AN XY: 74430

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.0496

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.00537

Gnomad4 NFE AF: 0.0123

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0129 Hom.: 10

Bravo AF: 0.00832

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0132

EpiControl AF: 0.0127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Asn615Asn in Exon 20 of EYA4: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 1.2% (87/7020) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs142721902). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	GeneDx	Feb 05, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Dilated cardiomyopathy 1J Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 10 Benign:1

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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.8
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs142721902; hg19: chr6-133849868;