rs121909202

chr8-71244662-G-Achr8-71244662-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000503.6(EYA1):c.1081C>T(p.Arg361Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EYA1 NM_000503.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.76

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 8-71244662-G-A is Pathogenic according to our data. Variant chr8-71244662-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-71244662-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYA1	NM_000503.6	c.1081C>T	p.Arg361Ter	stop_gained	12/18	ENST00000340726.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYA1	ENST00000340726.8	c.1081C>T	p.Arg361Ter	stop_gained	12/18	1	NM_000503.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456968 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 725014

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: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18177466, 25525159, 26969326, 34387732, 31581539, 21280147, 16691597) -

Branchiootorenal syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.1081C>T;p.(Arg361*) variant creates a premature translational stop signal in EYA1 gene. It is expected to result in an absent or disrupted protein product -PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 7943; PMID: 26969326;18177466; 21280147) - PS4. This variant is not present in population databases (rs121909202, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2008	- -

Branchiootic syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2021

The c.1081C>T (p.R361*) alteration, located in exon 12 (coding exon 10) of the EYA1 gene, consists of a C to T substitution at nucleotide position 1081. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 361. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The EYA1 c.1081C>T alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple patients with branchio-oto-renal (BOR) syndrome (Krug, 2011; Olavarrieta, 2008; Orten, 2008; Sloan-Heggen, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

Melnick-Fraser syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2023

ClinVar contains an entry for this variant (Variation ID: 7943). This variant is also known as Arg328X. This premature translational stop signal has been observed in individual(s) with branchio-oto-renal syndrome (PMID: 16691597, 18177466, 21280147, 26969326). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg361*) in the EYA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EYA1 are known to be pathogenic (PMID: 10464653, 18220287). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.68	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A
Vest4		0.95
GERP RS		-0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs121909202; hg19: chr8-72156897;