rs121909202

Variant names:

• chr8-71244662-G-A
• rs121909202
• NM_000503.6:c.1081C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-71244662-G-A
• chr8-71244662-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000503.6(EYA1):​c.1081C>T​(p.Arg361*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 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:11
• Conservation: PhyloP100: 1.76
• Publications: 12 publications found

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]

EYA1 Gene-Disease associations (from GenCC):

• branchio-oto-renal syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• branchiootorenal syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• branchiootic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-71244662-G-A is Pathogenic according to our data. Variant chr8-71244662-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000503.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA1	NM_000503.6	MANE Select	c.1081C>T	p.Arg361*	stop_gained	Exon 12 of 18	NP_000494.2
	EYA1	NM_001370333.1		c.1168C>T	p.Arg390*	stop_gained	Exon 13 of 19	NP_001357262.1	A0A2R8Y6K4
	EYA1	NM_001370334.1		c.1081C>T	p.Arg361*	stop_gained	Exon 14 of 20	NP_001357263.1	Q99502-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA1	ENST00000340726.8	TSL:1 MANE Select	c.1081C>T	p.Arg361*	stop_gained	Exon 12 of 18	ENSP00000342626.3	Q99502-1
	EYA1	ENST00000388742.8	TSL:1	c.1081C>T	p.Arg361*	stop_gained	Exon 11 of 17	ENSP00000373394.4	Q99502-1
	EYA1	ENST00000419131.6	TSL:1	c.1035+25078C>T		intron	N/A	ENSP00000410176.1	Q99502-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250018 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107884

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Branchiootic syndrome 1 (2)
2	-	-	Branchiootorenal syndrome 1 (2)
2	-	-	EYA1-related disorder (2)
2	-	-	not provided (2)
1	-	-	Branchiootic syndrome 1;C3714941:Otofaciocervical syndrome 1;C4551702:Branchiootorenal syndrome 1 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Melnick-Fraser syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.8
Vest4		0.95
GERP RS		-0.32
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121909202; hg19: chr8-72156897;