6-133506134-TCCGCA-T

Variant names:

• chr6-133506134-TCCGCA-T
• rs1562498114
• NM_004100.5:c.1221_1225delCCGCA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004100.5(EYA4):​c.1221_1225delCCGCA​(p.Arg408GlyfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L407L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EYA4 NM_004100.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.69
• Publications: 0 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]

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-133506134-TCCGCA-T is Pathogenic according to our data. Variant chr6-133506134-TCCGCA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 572508.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1221_1225delCCGCA	p.Arg408GlyfsTer6	frameshift	Exon 14 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.1239_1243delCCGCA	p.Arg414GlyfsTer6	frameshift	Exon 14 of 20	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.1221_1225delCCGCA	p.Arg408GlyfsTer6	frameshift	Exon 14 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.1221_1225delCCGCA	p.Arg408GlyfsTer6	frameshift	Exon 14 of 20	ENSP00000347434.7	O95677-1
	TARID	ENST00000607033.5	TSL:1	n.2471_2475delTGCGG		non_coding_transcript_exon	Exon 8 of 9
	EYA4	ENST00000531901.5	TSL:2	c.1239_1243delCCGCA	p.Arg414GlyfsTer6	frameshift	Exon 14 of 20	ENSP00000432770.1	F2Z2Y1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Dilated cardiomyopathy 1J (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1562498114; hg19: chr6-133827272;