rs1445404

Positions:

• chr8-71354848-G-A
• chr8-71354848-G-C
• chr8-71354848-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000340726.8(EYA1):​c.58C>T​(p.Pro20Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EYA1 ENST00000340726.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.95

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYA1	NM_000503.6	c.58C>T	p.Pro20Ser	missense_variant	3/18	ENST00000340726.8	NP_000494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8	c.58C>T	p.Pro20Ser	missense_variant	3/18	1	NM_000503.6	ENSP00000342626	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461416 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	0.0086	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;T;T;.;.;T;T;.;.;.;.
Eigen	Benign	0.063
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;.;D;D;.;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;N;N;N;.;N;N;.;.;.;.
MutationTaster	Benign	4.7e-10	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.82	N;.;N;N;N;.;.;.;.;.;N
REVEL	Benign	0.25
Sift	Benign	0.10	T;.;T;T;T;.;.;.;.;.;T
Sift4G	Benign	1.0	T;.;T;T;T;.;.;.;.;.;T
Polyphen		0.037	B;B;B;.;B;B;B;.;.;.;.
Vest4		0.53
MutPred		0.21		Gain of phosphorylation at P20 (P = 0.0055);Gain of phosphorylation at P20 (P = 0.0055);Gain of phosphorylation at P20 (P = 0.0055);Gain of phosphorylation at P20 (P = 0.0055);Gain of phosphorylation at P20 (P = 0.0055);Gain of phosphorylation at P20 (P = 0.0055);Gain of phosphorylation at P20 (P = 0.0055);.;.;.;Gain of phosphorylation at P20 (P = 0.0055);
MVP		0.53
MPC		0.66
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.12
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1445404; hg19: chr8-72267083;