8-71215405-A-T

Position:

• chr8-71215405-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000503.6(EYA1):​c.1579T>A​(p.Tyr527Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y527C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EYA1 NM_000503.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.22

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 8-71215405-A-T is Pathogenic according to our data. Variant chr8-71215405-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48103.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-71215405-A-T is described in Lovd as [Pathogenic]. Variant chr8-71215405-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA1	NM_000503.6	c.1579T>A	p.Tyr527Asn	missense_variant	16/18	ENST00000340726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8	c.1579T>A	p.Tyr527Asn	missense_variant	16/18	1	NM_000503.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 20, 2017

p.Tyr527Asn, c.1579T>A (EYA1; NM_172058.2; Chr8g.72127640A>T; GRCh37): The p.Tyr 527Asn variant in EYA1 has been reported in 2 individuals with Branchio-oto-rena l syndrome and segregated with disease in 3 affected relatives (Orten 2008, LMM data). This variant has not been reported in large population studies. A differ ent amino acid change at the same codon (p.Tyr527Cys) was identified in two prob ands with Branchio-oto-renal syndrome, suggesting that a change of amino acid at this position may not be tolerated (Orten 2008, Krup 2011). Computational predi ction tools and conservation analysis suggest that this variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity on its own. In summary, although additional studies are required to fully es tablish its clinical significance, this variant is likely pathogenic for autosom al dominant Branchio-oto-renal syndrome based on its occurrence in multiple affe cted individuals with clinical features of BOR, segregation with phenotypes in f amily members, extremely low allele frequency in the general population, and sup portive functional predictions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;D;.;.;.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;.;.;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;M;.;.;.;M;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D;.;D;D;D;D;.;.;.;.;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;D;D;D;.;.;.;.;.;D;D
Sift4G	Pathogenic	0.0	D;.;D;D;D;D;.;.;.;.;.;D;D
Polyphen		1.0	D;D;D;.;D;D;D;D;.;.;.;.;.
Vest4		0.99
MutPred		0.93		Gain of disorder (P = 0.0314);Gain of disorder (P = 0.0314);Gain of disorder (P = 0.0314);.;.;.;Gain of disorder (P = 0.0314);Gain of disorder (P = 0.0314);.;.;.;.;.;
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.95

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: rs397517918; hg19: chr8-72127640;