8-71215529-C-A

Variant names:

• chr8-71215529-C-A
• rs3735935
• NM_000503.6:c.1476-21G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000503.6(EYA1):​c.1476-21G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,610,736 control chromosomes in the GnomAD database, including 91,815 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8629 hom., cov: 33)
  • Exomes 𝑓: 0.32 (83186 hom.)
• Consequence: EYA1 NM_000503.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.593
• Publications: 11 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: ClinGen, Orphanet
• branchiootorenal syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• branchiootic syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• branchiootic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285579 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-71215529-C-A is Benign according to our data. Variant chr8-71215529-C-A is described in ClinVar as Benign. ClinVar VariationId is 1253275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA1	NM_000503.6	c.1476-21G>T		intron_variant	Intron 15 of 17	ENST00000340726.8	NP_000494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8	c.1476-21G>T		intron_variant	Intron 15 of 17	1	NM_000503.6	ENSP00000342626.3

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48658 AN: 151902 Hom.: 8613 Cov.: 33

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.339

Gnomad EAS AF: 0.758

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.378 AC: 94834 AN: 250698 AF XY: 0.374

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.346

Gnomad EAS exome AF: 0.761

Gnomad FIN exome AF: 0.346

Gnomad NFE exome AF: 0.289

Gnomad OTH exome AF: 0.338

GnomAD4 exome AF: 0.323 AC: 471592 AN: 1458716 Hom.: 83186 Cov.: 33 AF XY: 0.325 AC XY: 236222 AN XY: 725890

African (AFR) AF: 0.238 AC: 7939 AN: 33422

American (AMR) AF: 0.499 AC: 22301 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 9104 AN: 26104

East Asian (EAS) AF: 0.758 AC: 30057 AN: 39676

South Asian (SAS) AF: 0.435 AC: 37498 AN: 86198

European-Finnish (FIN) AF: 0.337 AC: 18021 AN: 53396

Middle Eastern (MID) AF: 0.279 AC: 1605 AN: 5762

European-Non Finnish (NFE) AF: 0.293 AC: 324687 AN: 1109238

Other (OTH) AF: 0.338 AC: 20380 AN: 60236

GnomAD4 genome AF: 0.320 AC: 48712 AN: 152020 Hom.: 8629 Cov.: 33 AF XY: 0.329 AC XY: 24434 AN XY: 74318

African (AFR) AF: 0.246 AC: 10188 AN: 41456

American (AMR) AF: 0.414 AC: 6318 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.339 AC: 1178 AN: 3470

East Asian (EAS) AF: 0.759 AC: 3921 AN: 5168

South Asian (SAS) AF: 0.469 AC: 2250 AN: 4800

European-Finnish (FIN) AF: 0.369 AC: 3897 AN: 10568

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19800 AN: 67980

Other (OTH) AF: 0.333 AC: 702 AN: 2108

Alfa AF: 0.275 Hom.: 3482

Bravo AF: 0.322

Asia WGS AF: 0.615 AC: 2142 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Branchiootic syndrome 1 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Branchiootorenal syndrome 1 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Otofaciocervical syndrome 1 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.3
DANN	Benign	0.67
PhyloP100		0.59
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3735935; hg19: chr8-72127764; COSMIC: COSV58164182; COSMIC: COSV58164182;