chr6-133468627-C-T

Variant names:

• chr6-133468627-C-T
• rs41286200
• NM_004100.5:c.866C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_004100.5(EYA4):​c.866C>T​(p.Thr289Met) variant causes a missense change. The variant allele was found at a frequency of 0.000856 in 1,612,548 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (3 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:8
• Conservation: PhyloP100: 5.72

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08106679).
• BP6: Variant 6-133468627-C-T is Benign according to our data. Variant chr6-133468627-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163446.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Likely_pathogenic=1, Benign=2, Uncertain_significance=3}. Variant chr6-133468627-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000677 (103/152190) while in subpopulation NFE AF= 0.00113 (77/67986). AF 95% confidence interval is 0.000929. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5	c.866C>T	p.Thr289Met	missense_variant	Exon 11 of 20	ENST00000355286.12	NP_004091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12	c.866C>T	p.Thr289Met	missense_variant	Exon 11 of 20	1	NM_004100.5	ENSP00000347434.7

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000638 AC: 160 AN: 250734 Hom.: 1 AF XY: 0.000605 AC XY: 82 AN XY: 135492

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000875 AC: 1278 AN: 1460358 Hom.: 3 Cov.: 32 AF XY: 0.000855 AC XY: 621 AN XY: 726526

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000762

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000677 AC: 103 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000780 AC XY: 58 AN XY: 74404

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000927 Hom.: 0

Bravo AF: 0.000771

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000626 AC: 76

EpiCase AF: 0.00126

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Sep 02, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23861362, 28798025) -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EYA4: BS1, BS2 -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Autosomal dominant nonsyndromic hearing loss 10 Pathogenic:1 Benign:1

May 08, 2024

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Likely pathogenic by Deafness Variation Database -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dilated cardiomyopathy 1J Uncertain:1 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:2

Feb 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Thr289Met variant in EYA4 is classified as benign because it has been identified in 0.1% of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

Dec 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EYA4 c.866C>T (p.Thr289Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 250734 control chromosomes, predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 70 fold of the estimated maximal expected allele frequency for a pathogenic variant in EYA4 causing Dilated Cardiomyopathy phenotype (1.6e-05). To our knowledge, no experimental evidence of c.866C>T demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 163446). Based on the evidence outlined above, the variant was classified as likely benign. -

EYA4-related disorder Benign:1

Sep 21, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

May 31, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	.;T;T;.;T;.;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.081	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.9	.;.;L;L;L;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.2	N;N;N;N;.;.;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.039	D;D;D;D;.;.;D;D
Sift4G	Benign	0.21	T;T;T;T;.;.;T;T
Polyphen		1.0, 1.0, 0.99, 0.99	.;D;D;D;D;D;D;.
Vest4		0.70
MVP		0.86
MPC		0.52
ClinPred		0.24	T
GERP RS		5.7
Varity_R		0.13
gMVP		0.38

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: rs41286200; hg19: chr6-133789765; COSMIC: COSV62063819; COSMIC: COSV62063819;