rs752023028

Positions:

• chr6-133468572-C-A
• chr6-133468572-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004100.5(EYA4):​c.811C>A​(p.Pro271Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P271P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.73

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39898622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA4	NM_004100.5	c.811C>A	p.Pro271Thr	missense_variant	11/20	ENST00000355286.12	NP_004091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12	c.811C>A	p.Pro271Thr	missense_variant	11/20	1	NM_004100.5	ENSP00000347434	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456038 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.064	.;T;D;.;D;.;T;T
Eigen	Benign	-0.098
Eigen_PC	Benign	0.076
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;.;D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.1	.;.;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.9	N;N;N;N;.;.;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.088	T;T;T;T;.;.;T;T
Sift4G	Benign	0.71	T;T;T;T;.;.;T;T
Polyphen		0.0020, 0.0010, 0.0	.;B;B;B;B;B;B;.
Vest4		0.44
MutPred		0.33		.;.;Loss of phosphorylation at T274 (P = 0.1787);Loss of phosphorylation at T274 (P = 0.1787);Loss of phosphorylation at T274 (P = 0.1787);.;Loss of phosphorylation at T274 (P = 0.1787);.;
MVP		0.78
MPC		0.17
ClinPred		0.79	D
GERP RS		4.6
Varity_R		0.24
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs752023028; hg19: chr6-133789710;