rs35562371

Variant names:

• chr6-133446649-C-G
• rs35562371
• NM_004100.5:c.103C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-133446649-C-G
• chr6-133446649-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_004100.5(EYA4):​c.103C>G​(p.Leu35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,628 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). Synonymous variant affecting the same amino acid position (i.e. L35L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: EYA4 NM_004100.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.10
• 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]

EYA4 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 10

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36113426).
• BP6: Variant 6-133446649-C-G is Benign according to our data. Variant chr6-133446649-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 839376.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000848 (124/1461486) while in subpopulation NFE AF = 0.000105 (117/1111706). AF 95% confidence interval is 0.0000894. There are 0 homozygotes in GnomAdExome4. There are 57 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 8 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.103C>G	p.Leu35Val	missense	Exon 4 of 20	NP_004091.3
	EYA4	NM_001301013.2		c.103C>G	p.Leu35Val	missense	Exon 4 of 20	NP_001287942.1	F2Z2Y1
	EYA4	NM_172105.4		c.103C>G	p.Leu35Val	missense	Exon 4 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.103C>G	p.Leu35Val	missense	Exon 4 of 20	ENSP00000347434.7	O95677-1
	EYA4	ENST00000531901.5	TSL:2	c.103C>G	p.Leu35Val	missense	Exon 4 of 20	ENSP00000432770.1	F2Z2Y1
	EYA4	ENST00000883055.1		c.103C>G	p.Leu35Val	missense	Exon 5 of 21	ENSP00000553114.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152142 Hom.: 0 Cov.: 32

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251396 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000848 AC: 124 AN: 1461486 Hom.: 0 Cov.: 31 AF XY: 0.0000784 AC XY: 57 AN XY: 727062

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000105 AC: 117 AN: 1111706

Other (OTH) AF: 0.000116 AC: 7 AN: 60388

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74316

African (AFR) AF: 0.0000483 AC: 2 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000430 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1J (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	1.0	L
PhyloP100		3.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.48
Sift	Benign	0.40	T
Sift4G	Benign	0.86	T
Polyphen		0.45	B
Vest4		0.53
MutPred		0.097		Gain of phosphorylation at S37 (P = 0.1848)
MVP		0.95
MPC		0.16
ClinPred		0.47	T
GERP RS		4.1
Varity_R		0.42
gMVP		0.35
Mutation Taster		=77/23	polymorphism

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: rs35562371; hg19: chr6-133767787;