rs121909200

chr8-71215630-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000503.6(EYA1):c.1459T>C(p.Ser487Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S487L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EYA1 NM_000503.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.68

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000503.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-71215629-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 8-71215630-A-G is Pathogenic according to our data. Variant chr8-71215630-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7940.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-71215630-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA1	NM_000503.6	c.1459T>C	p.Ser487Pro	missense_variant	15/18	ENST00000340726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8	c.1459T>C	p.Ser487Pro	missense_variant	15/18	1	NM_000503.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251282 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135788

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461782 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Melnick-Fraser syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 21, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects EYA1 function (PMID: 11734542, 15802522, 16797546, 24489909). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EYA1 protein function. ClinVar contains an entry for this variant (Variation ID: 7940). This variant is also known as S454P. This missense change has been observed in individuals with branchiootorenal syndrome (PMID: 8566479, 9361030, 10464653; Invitae). This variant is present in population databases (rs121909200, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 487 of the EYA1 protein (p.Ser487Pro). -

Branchiootorenal syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D;D;.;.;.;D;D;.;.;.;.;.
Eigen	Benign	0.011
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.4	L;L;L;.;.;.;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D;.;D;D;D;D;.;.;.;.;.;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.091	T;.;T;T;T;T;.;.;.;.;.;T;T
Sift4G	Benign	0.091	T;.;T;T;T;T;.;.;.;.;.;T;T
Polyphen		0.21	B;B;B;.;B;B;B;B;.;.;.;.;.
Vest4		0.83
MutPred		0.90		Loss of stability (P = 0.1159);Loss of stability (P = 0.1159);Loss of stability (P = 0.1159);.;.;.;Loss of stability (P = 0.1159);Loss of stability (P = 0.1159);.;.;.;.;.;
MVP		0.92
MPC		0.39
ClinPred		0.77	D
GERP RS		3.3
Varity_R		0.60
gMVP		0.90

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: rs121909200; hg19: chr8-72127865;