6-133481873-C-G

Variant names:

• chr6-133481873-C-G
• rs212772
• NM_004100.5:c.1107+274C>G

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.1107+274C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 151,914 control chromosomes in the GnomAD database, including 10,870 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.36 (10870 hom., cov: 32)
• Consequence: EYA4 NM_004100.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.585
• 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]

EYA4 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy 1J

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-133481873-C-G is Benign according to our data. Variant chr6-133481873-C-G is described in ClinVar as Benign. ClinVar VariationId is 1262176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA4	NM_004100.5	c.1107+274C>G		intron_variant	Intron 12 of 19	ENST00000355286.12	NP_004091.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA4	ENST00000355286.12	c.1107+274C>G		intron_variant	Intron 12 of 19	1	NM_004100.5	ENSP00000347434.7

Frequencies

GnomAD3 genomes AF: 0.356 AC: 53980 AN: 151794 Hom.: 10869 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.359

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.361

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

GnomAD4 genome AF: 0.355 AC: 54002 AN: 151914 Hom.: 10870 Cov.: 32 AF XY: 0.354 AC XY: 26283 AN XY: 74230

African (AFR) AF: 0.182 AC: 7542 AN: 41428

American (AMR) AF: 0.359 AC: 5474 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1550 AN: 3468

East Asian (EAS) AF: 0.207 AC: 1070 AN: 5160

South Asian (SAS) AF: 0.233 AC: 1124 AN: 4818

European-Finnish (FIN) AF: 0.493 AC: 5192 AN: 10534

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.454 AC: 30827 AN: 67934

Other (OTH) AF: 0.362 AC: 764 AN: 2108

Alfa AF: 0.240 Hom.: 453

Bravo AF: 0.357

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.30
DANN	Benign	0.45
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism (auto)

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: rs212772; hg19: chr6-133803011;