rs121909197

Positions:

• chr8-71211215-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000503.6(EYA1):​c.1639A>G​(p.Arg547Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EYA1 NM_000503.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.91

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]

LOC105375894 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 8-71211215-T-C is Pathogenic according to our data. Variant chr8-71211215-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 7936.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-71211215-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA1	NM_000503.6	c.1639A>G	p.Arg547Gly	missense_variant	17/18	ENST00000340726.8
LOC105375894	XR_007060958.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8	c.1639A>G	p.Arg547Gly	missense_variant	17/18	1	NM_000503.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Anterior segment anomalies and cataract Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 12, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D;D;.;.;.;D;D;.;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;.;.;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.6	M;M;M;.;.;.;M;M;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.5	D;.;D;D;D;D;.;.;.;.;.;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.018	D;.;D;D;D;D;.;.;.;.;.;D;D
Sift4G	Uncertain	0.0020	D;.;D;D;D;D;.;.;.;.;.;D;D
Polyphen		0.99	D;D;D;.;P;D;D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.83		Loss of MoRF binding (P = 0.0124);Loss of MoRF binding (P = 0.0124);Loss of MoRF binding (P = 0.0124);.;.;.;Loss of MoRF binding (P = 0.0124);Loss of MoRF binding (P = 0.0124);.;.;.;.;.;
MVP		0.99
MPC		0.94
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.61
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909197; hg19: chr8-72123450;