rs752023028

Variant names:

• chr6-133468572-C-A
• rs752023028
• NM_004100.5:c.811C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P271A) has been classified as Uncertain significance.

• 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
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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: Uncertain_significance. The variant received 1 ACMG points.

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

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	NM_004100.5	MANE Select	c.811C>A	p.Pro271Thr	missense	Exon 11 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.811C>A	p.Pro271Thr	missense	Exon 11 of 20	NP_001287942.1
	EYA4	NM_172105.4		c.811C>A	p.Pro271Thr	missense	Exon 11 of 20	NP_742103.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA4	ENST00000355286.12	TSL:1 MANE Select	c.811C>A	p.Pro271Thr	missense	Exon 11 of 20	ENSP00000347434.7
	EYA4	ENST00000531901.5	TSL:2	c.811C>A	p.Pro271Thr	missense	Exon 11 of 20	ENSP00000432770.1
	EYA4	ENST00000431403.3	TSL:5	c.742C>A	p.Pro248Thr	missense	Exon 10 of 19	ENSP00000404558.3

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33226

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107056

Other (OTH) AF: 0.00 AC: 0 AN: 60150

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.098
Eigen_PC	Benign	0.076
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.7
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.48
Sift	Benign	0.088	T
Sift4G	Benign	0.71	T
Polyphen		0.0020	B
Vest4		0.44
MutPred		0.33		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
Mutation Taster		=33/67	disease causing

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: rs752023028; hg19: chr6-133789710;