rs757995893

Variant names:

• chr6-133515430-C-A
• NM_004100.5:c.1611C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-133515430-C-A
• chr6-133515430-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004100.5(EYA4):​c.1611C>A​(p.Ser537Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,384,746 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.993

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]

TARID (HGNC:50506): (TCF21 antisense RNA inducing promoter demethylation)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5	c.1611C>A	p.Ser537Arg	missense_variant	Exon 17 of 20	ENST00000355286.12	NP_004091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12	c.1611C>A	p.Ser537Arg	missense_variant	Exon 17 of 20	1	NM_004100.5	ENSP00000347434.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1384746 Hom.: 0 Cov.: 23 AF XY: 0.00000144 AC XY: 1 AN XY: 693656

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: 0.00000192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.097	.;T;D;.;D;.;D;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.1	.;.;L;L;L;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.61	N;N;N;N;.;.;N;N
REVEL	Uncertain	0.58
Sift	Uncertain	0.012	D;D;T;T;.;.;T;D
Sift4G	Benign	0.065	T;D;T;T;.;.;T;T
Polyphen		0.52, 0.99	.;P;P;P;P;D;P;.
Vest4		0.68
MutPred		0.45		.;.;.;.;.;.;Gain of MoRF binding (P = 0.0348);.;
MVP		0.78
MPC		2.4
ClinPred		0.85	D
GERP RS		0.40
Varity_R		0.24
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-133836568;