rs1554565600

Variant names:

• chr8-71354818-T-C
• rs1554565600
• NM_000503.6:c.88A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000503.6(EYA1):​c.88A>G​(p.Ile30Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EYA1 NM_000503.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.84
• Publications: 0 publications found

Genes affected

EYA1 (HGNC:3519): (EYA transcriptional coactivator and phosphatase 1) This gene encodes a member of the eyes absent (EYA) family of proteins. The encoded protein may play a role in the developing kidney, branchial arches, eye, and ear. Mutations of this gene have been associated with branchiootorenal dysplasia syndrome, branchiootic syndrome, and sporadic cases of congenital cataracts and ocular anterior segment anomalies. A similar protein in mice can act as a transcriptional activator. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2013]

EYA1 Gene-Disease associations (from GenCC):

• branchio-oto-renal syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• branchiootorenal syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• branchiootic syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• branchiootic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106156796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA1	NM_000503.6	c.88A>G	p.Ile30Val	missense_variant	Exon 3 of 18	ENST00000340726.8	NP_000494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8	c.88A>G	p.Ile30Val	missense_variant	Exon 3 of 18	1	NM_000503.6	ENSP00000342626.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Sep 14, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile30Val variant in EYA1 has not been previously reported in individuals w ith hearing loss or in large population studies. Computational prediction tools and conservation analysis suggest that the variant may not impact the protein, t hough this information is not predictive enough to rule out pathogenicity. In su mmary, the clinical significance of the p.Ile30Val variant is uncertain. -

not provided Uncertain:1

May 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;T;.;.;T;T;.;.;.;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	.;.;.;D;D;.;D;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;L;.;L;L;.;.;.;.
PhyloP100		2.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.020	N;.;N;N;N;.;.;.;.;.;N
REVEL	Benign	0.064
Sift	Benign	0.076	T;.;T;T;T;.;.;.;.;.;T
Sift4G	Benign	1.0	T;.;T;T;T;.;.;.;.;.;T
Polyphen		0.011	B;B;B;.;B;B;B;.;.;.;.
Vest4		0.14
MutPred		0.14		Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);Gain of phosphorylation at S34 (P = 0.1856);.;.;.;Gain of phosphorylation at S34 (P = 0.1856);
MVP		0.42
MPC		0.21
ClinPred		0.59	D
GERP RS		1.8
Varity_R		0.055
gMVP		0.34
Mutation Taster		=89/11	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: rs1554565600; hg19: chr8-72267053; COSMIC: COSV100378944;