rs193920835

Positions:

• chr8-71244636-C-A
• chr8-71244636-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000503.6(EYA1):​c.1107G>T​(p.Leu369Phe) 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 Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EYA1 NM_000503.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 4.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA1	NM_000503.6	c.1107G>T	p.Leu369Phe	missense_variant	12/18	ENST00000340726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8	c.1107G>T	p.Leu369Phe	missense_variant	12/18	1	NM_000503.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;D;D;.;.;D;D;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.6	M;M;M;.;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.1	D;.;D;D;D;.;.;.;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;.;D;D;D;.;.;.;D;D
Sift4G	Uncertain	0.0050	D;.;D;D;D;.;.;.;D;D
Polyphen		1.0	D;D;D;D;D;D;D;.;.;.
Vest4		0.93
MutPred		0.57		Gain of catalytic residue at H373 (P = 0.1844);Gain of catalytic residue at H373 (P = 0.1844);Gain of catalytic residue at H373 (P = 0.1844);.;.;Gain of catalytic residue at H373 (P = 0.1844);Gain of catalytic residue at H373 (P = 0.1844);.;.;.;
MVP		0.83
MPC		0.87
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.62
gMVP		0.83

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: rs193920835; hg19: chr8-72156871; COSMIC: COSV58175614;