chr6-133528730-C-T

Variant names:

• chr6-133528730-C-T
• rs142721902
• NM_004100.5:c.1845C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004100.5(EYA4):​c.1845C>T​(p.Asn615Asn) variant causes a synonymous change. The variant allele was found at a frequency of 0.0124 in 1,611,356 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (15 hom., cov: 32)
  • Exomes 𝑓: 0.013 (186 hom.)
• Consequence: EYA4 NM_004100.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 5.01
• 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]

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 6-133528730-C-T is Benign according to our data. Variant chr6-133528730-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00898 (1367/152254) while in subpopulation SAS AF = 0.0213 (103/4826). AF 95% confidence interval is 0.018. There are 15 homozygotes in GnomAd4. There are 633 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1367 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.1845C>T	p.Asn615Asn	synonymous	Exon 20 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.1863C>T	p.Asn621Asn	synonymous	Exon 20 of 20	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.1845C>T	p.Asn615Asn	synonymous	Exon 20 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.1845C>T	p.Asn615Asn	synonymous	Exon 20 of 20	ENSP00000347434.7	O95677-1
	TARID	ENST00000607033.5	TSL:1	n.2261+7050G>A		intron	N/A
	EYA4	ENST00000531901.5	TSL:2	c.1863C>T	p.Asn621Asn	synonymous	Exon 20 of 20	ENSP00000432770.1	F2Z2Y1

Frequencies

GnomAD3 genomes AF: 0.00899 AC: 1367 AN: 152136 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.0496

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.00537

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.0117 AC: 2935 AN: 251228 AF XY: 0.0127

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.0414

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0127 AC: 18598 AN: 1459102 Hom.: 186 Cov.: 31 AF XY: 0.0133 AC XY: 9636 AN XY: 726066

African (AFR) AF: 0.00216 AC: 72 AN: 33396

American (AMR) AF: 0.00434 AC: 194 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0422 AC: 1101 AN: 26098

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39680

South Asian (SAS) AF: 0.0249 AC: 2146 AN: 86210

European-Finnish (FIN) AF: 0.00391 AC: 209 AN: 53416

Middle Eastern (MID) AF: 0.0259 AC: 149 AN: 5764

European-Non Finnish (NFE) AF: 0.0125 AC: 13879 AN: 1109544

Other (OTH) AF: 0.0141 AC: 847 AN: 60280

GnomAD4 genome AF: 0.00898 AC: 1367 AN: 152254 Hom.: 15 Cov.: 32 AF XY: 0.00850 AC XY: 633 AN XY: 74430

African (AFR) AF: 0.00236 AC: 98 AN: 41556

American (AMR) AF: 0.00497 AC: 76 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0496 AC: 172 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.0213 AC: 103 AN: 4826

European-Finnish (FIN) AF: 0.00537 AC: 57 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 840 AN: 68018

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.0129 Hom.: 10

Bravo AF: 0.00832

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0132

EpiControl AF: 0.0127

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	2	Dilated cardiomyopathy 1J (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 10 (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	5.8
DANN	Benign	0.64
PhyloP100		5.0
Mutation Taster		=88/12	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs142721902; hg19: chr6-133849868;