6-133506010-T-C

Variant names:

• chr6-133506010-T-C
• rs6929656
• NM_004100.5:c.1192-96T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004100.5(EYA4):​c.1192-96T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.928 in 800,300 control chromosomes in the GnomAD database, including 345,435 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.94 (66902 hom., cov: 31)
  • Exomes 𝑓: 0.93 (278533 hom.)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.40
• Publications: 6 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-133506010-T-C is Benign according to our data. Variant chr6-133506010-T-C is described in ClinVar as Benign. ClinVar VariationId is 1296321.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

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.1192-96T>C		intron	N/A	NP_004091.3
	EYA4	NM_001301013.2		c.1210-96T>C		intron	N/A	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.1192-96T>C		intron	N/A	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.1192-96T>C		intron	N/A	ENSP00000347434.7	O95677-1
	TARID	ENST00000607033.5	TSL:1	n.2531+69A>G		intron	N/A
	EYA4	ENST00000531901.5	TSL:2	c.1210-96T>C		intron	N/A	ENSP00000432770.1	F2Z2Y1

Frequencies

GnomAD3 genomes AF: 0.936 AC: 142439 AN: 152098 Hom.: 66839 Cov.: 31

Gnomad AFR AF: 0.983

Gnomad AMI AF: 0.888

Gnomad AMR AF: 0.940

Gnomad ASJ AF: 0.965

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.982

Gnomad FIN AF: 0.911

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.902

Gnomad OTH AF: 0.937

GnomAD4 exome AF: 0.926 AC: 600410 AN: 648084 Hom.: 278533 AF XY: 0.929 AC XY: 325497 AN XY: 350474

African (AFR) AF: 0.983 AC: 16623 AN: 16908

American (AMR) AF: 0.958 AC: 38574 AN: 40272

Ashkenazi Jewish (ASJ) AF: 0.964 AC: 19770 AN: 20508

East Asian (EAS) AF: 1.00 AC: 34438 AN: 34442

South Asian (SAS) AF: 0.983 AC: 66481 AN: 67628

European-Finnish (FIN) AF: 0.911 AC: 45061 AN: 49466

Middle Eastern (MID) AF: 0.952 AC: 3800 AN: 3990

European-Non Finnish (NFE) AF: 0.903 AC: 344905 AN: 381806

Other (OTH) AF: 0.930 AC: 30758 AN: 33064

GnomAD4 genome AF: 0.937 AC: 142563 AN: 152216 Hom.: 66902 Cov.: 31 AF XY: 0.939 AC XY: 69891 AN XY: 74422

African (AFR) AF: 0.983 AC: 40854 AN: 41552

American (AMR) AF: 0.940 AC: 14357 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.965 AC: 3352 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5172

South Asian (SAS) AF: 0.983 AC: 4738 AN: 4822

European-Finnish (FIN) AF: 0.911 AC: 9655 AN: 10604

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.902 AC: 61375 AN: 68006

Other (OTH) AF: 0.938 AC: 1981 AN: 2112

Alfa AF: 0.925 Hom.: 53563

Bravo AF: 0.940

Asia WGS AF: 0.989 AC: 3441 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.62
DANN	Benign	0.61
PhyloP100		-1.4
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs6929656; hg19: chr6-133827148;