dbSNP rs118166702: EYA4:c.1617-11C>T (chr6-133523045-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004100.5(EYA4):c.1617-11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,605,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

EYA4
NM_004100.5 intron

Scores

Splicing: ADA: 0.09076

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 1.33

Publications

1 publications found

Variant links:

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 links:

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

TARID links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 6-133523045-C-T is Benign according to our data. Variant chr6-133523045-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227369.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000191 (29/152196) while in subpopulation NFE AF = 0.000397 (27/67986). AF 95% confidence interval is 0.00028. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 29 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EYA4	NM_004100.5	MANE Select	c.1617-11C>T	intron	N/A	NP_004091.3
EYA4	NM_001301013.2		c.1635-11C>T	intron	N/A	NP_001287942.1	F2Z2Y1
EYA4	NM_172105.4		c.1617-11C>T	intron	N/A	NP_742103.1	O95677-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EYA4	ENST00000355286.12	TSL:1 MANE Select	c.1617-11C>T	intron	N/A	ENSP00000347434.7	O95677-1
TARID	ENST00000607033.5	TSL:1	n.2261+12735G>A	intron	N/A
EYA4	ENST00000531901.5	TSL:2	c.1635-11C>T	intron	N/A	ENSP00000432770.1	F2Z2Y1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000263

AC:

AN:

250820

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000538

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000325

AC:

473

AN:

1453610

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

225

AN XY:

723722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33270

American (AMR)

AF:

0.000157

AC:

AN:

44596

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

86076

European-Finnish (FIN)

AF:

0.0000563

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000405

AC:

447

AN:

1104904

Other (OTH)

AF:

0.000266

AC:

AN:

60092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000191

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41546

American (AMR)

AF:

0.00

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000251

Hom.:

Bravo

AF:

0.000174

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dilated cardiomyopathy 1J (2)

Autosomal dominant nonsyndromic hearing loss 10 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.091

dbscSNV1_RF

Benign

0.23

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over