rs146144708

Variant names:

• chr6-133481479-G-T
• rs146144708
• NM_004100.5:c.987G>T

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.987G>T​(p.Met329Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,613,852 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. M329L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: 0.0170
• Publications: 6 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=0.022367358).
• BP6: Variant 6-133481479-G-T is Benign according to our data. Variant chr6-133481479-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239632.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000191 (29/152220) while in subpopulation AMR AF = 0.000523 (8/15282). AF 95% confidence interval is 0.00026. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 29 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.987G>T	p.Met329Ile	missense	Exon 12 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.1005G>T	p.Met335Ile	missense	Exon 12 of 20	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.987G>T	p.Met329Ile	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.987G>T	p.Met329Ile	missense	Exon 12 of 20	ENSP00000347434.7	O95677-1
	EYA4	ENST00000531901.5	TSL:2	c.1005G>T	p.Met335Ile	missense	Exon 12 of 20	ENSP00000432770.1	F2Z2Y1
	EYA4	ENST00000883055.1		c.1005G>T	p.Met335Ile	missense	Exon 13 of 21	ENSP00000553114.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000288 AC: 72 AN: 250326 AF XY: 0.000325

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000320

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000218 AC: 319 AN: 1461632 Hom.: 2 Cov.: 31 AF XY: 0.000254 AC XY: 185 AN XY: 727134

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.000626 AC: 28 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000919 AC: 24 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00660 AC: 38 AN: 5760

European-Non Finnish (NFE) AF: 0.000169 AC: 188 AN: 1111814

Other (OTH) AF: 0.000629 AC: 38 AN: 60384

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74416

African (AFR) AF: 0.0000241 AC: 1 AN: 41534

American (AMR) AF: 0.000523 AC: 8 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000358 Hom.: 2

Bravo AF: 0.000291

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	2	-	Dilated cardiomyopathy 1J (2)
-	-	2	not specified (2)
-	1	-	Autosomal dominant nonsyndromic hearing loss 10 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PhyloP100		0.017
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.060	N
REVEL	Uncertain	0.33
Sift	Benign	0.49	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.36
MutPred		0.11		Loss of phosphorylation at T334 (P = 0.2538)
MVP		0.66
MPC		0.16
ClinPred		0.040	T
GERP RS		1.8
Varity_R		0.10
gMVP		0.14
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146144708; hg19: chr6-133802617;