NM_004100.5:c.979G>A

Variant names:

• chr6-133481471-G-A
• rs144415484
• NM_004100.5:c.979G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004100.5(EYA4):​c.979G>A​(p.Asp327Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D327H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 9.71
• Publications: 9 publications found

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]

EYA4 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1J

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01254791).
• BP6: Variant 6-133481471-G-A is Benign according to our data. Variant chr6-133481471-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191664.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000381 (58/152166) while in subpopulation EAS AF = 0.000386 (2/5180). AF 95% confidence interval is 0.0000683. There are 0 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 58 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004100.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	NM_004100.5	MANE Select	c.979G>A	p.Asp327Asn	missense	Exon 12 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.997G>A	p.Asp333Asn	missense	Exon 12 of 20	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.979G>A	p.Asp327Asn	missense	Exon 12 of 20	NP_742103.1	O95677-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	ENST00000355286.12	TSL:1 MANE Select	c.979G>A	p.Asp327Asn	missense	Exon 12 of 20	ENSP00000347434.7	O95677-1
	EYA4	ENST00000531901.5	TSL:2	c.997G>A	p.Asp333Asn	missense	Exon 12 of 20	ENSP00000432770.1	F2Z2Y1
	EYA4	ENST00000883055.1		c.997G>A	p.Asp333Asn	missense	Exon 13 of 21	ENSP00000553114.1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00406

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000496 AC: 124 AN: 250092 AF XY: 0.000473

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000223 AC: 326 AN: 1461592 Hom.: 0 Cov.: 31 AF XY: 0.000208 AC XY: 151 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.000291 AC: 13 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00468 AC: 250 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111784

Other (OTH) AF: 0.000315 AC: 19 AN: 60380

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74382

African (AFR) AF: 0.0000723 AC: 3 AN: 41492

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00406 AC: 43 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68012

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000156 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000338 AC: 41

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1J (1)
-	-	1	EYA4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	26
DANN	Benign	0.86
DEOGEN2	Benign	0.0020	T
Eigen	Benign	0.081
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.90	L
PhyloP100		9.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.16	N
REVEL	Uncertain	0.37
Sift	Benign	0.52	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.55
MVP		0.78
MPC		0.29
ClinPred		0.15	T
GERP RS		5.7
Varity_R		0.098
gMVP		0.31
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144415484; hg19: chr6-133802609; COSMIC: COSV62055504;