rs1445398

Variant names:

• chr8-71299060-T-C
• rs1445398
• NM_000503.6:c.813A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000503.6(EYA1):​c.813A>G​(p.Thr271Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0998 in 1,613,700 control chromosomes in the GnomAD database, including 11,653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (1078 hom., cov: 33)
  • Exomes 𝑓: 0.10 (10575 hom.)
• Consequence: EYA1 NM_000503.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.224
• Publications: 22 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 8-71299060-T-C is Benign according to our data. Variant chr8-71299060-T-C is described in ClinVar as Benign. ClinVar VariationId is 48109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.224 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

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.813A>G	p.Thr271Thr	synonymous	Exon 9 of 18	NP_000494.2
	EYA1	NM_001370333.1		c.900A>G	p.Thr300Thr	synonymous	Exon 10 of 19	NP_001357262.1	A0A2R8Y6K4
	EYA1	NM_001370334.1		c.813A>G	p.Thr271Thr	synonymous	Exon 11 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.813A>G	p.Thr271Thr	synonymous	Exon 9 of 18	ENSP00000342626.3	Q99502-1
	EYA1	ENST00000388742.8	TSL:1	c.813A>G	p.Thr271Thr	synonymous	Exon 8 of 17	ENSP00000373394.4	Q99502-1
	EYA1	ENST00000419131.6	TSL:1	c.798A>G	p.Thr266Thr	synonymous	Exon 8 of 16	ENSP00000410176.1	Q99502-3

Frequencies

GnomAD3 genomes AF: 0.0914 AC: 13906 AN: 152120 Hom.: 1078 Cov.: 33

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0646

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0849

Gnomad OTH AF: 0.0841

GnomAD2 exomes AF: 0.130 AC: 32752 AN: 251456 AF XY: 0.122

Gnomad AFR exome AF: 0.0348

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.0655

Gnomad EAS exome AF: 0.432

Gnomad FIN exome AF: 0.0688

Gnomad NFE exome AF: 0.0839

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.101 AC: 147121 AN: 1461462 Hom.: 10575 Cov.: 32 AF XY: 0.0993 AC XY: 72166 AN XY: 727068

African (AFR) AF: 0.0367 AC: 1229 AN: 33478

American (AMR) AF: 0.250 AC: 11186 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 1709 AN: 26132

East Asian (EAS) AF: 0.417 AC: 16543 AN: 39688

South Asian (SAS) AF: 0.0945 AC: 8151 AN: 86254

European-Finnish (FIN) AF: 0.0761 AC: 4064 AN: 53420

Middle Eastern (MID) AF: 0.0496 AC: 286 AN: 5768

European-Non Finnish (NFE) AF: 0.0878 AC: 97570 AN: 1111630

Other (OTH) AF: 0.106 AC: 6383 AN: 60380

GnomAD4 genome AF: 0.0914 AC: 13916 AN: 152238 Hom.: 1078 Cov.: 33 AF XY: 0.0939 AC XY: 6988 AN XY: 74432

African (AFR) AF: 0.0386 AC: 1603 AN: 41560

American (AMR) AF: 0.177 AC: 2706 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 199 AN: 3470

East Asian (EAS) AF: 0.436 AC: 2243 AN: 5144

South Asian (SAS) AF: 0.106 AC: 513 AN: 4822

European-Finnish (FIN) AF: 0.0646 AC: 685 AN: 10604

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0848 AC: 5771 AN: 68020

Other (OTH) AF: 0.0847 AC: 179 AN: 2114

Alfa AF: 0.0908 Hom.: 2773

Bravo AF: 0.103

Asia WGS AF: 0.250 AC: 867 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Branchiootic syndrome 1 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Otofaciocervical syndrome 1 (2)
-	-	1	Branchiootorenal syndrome 1 (1)
-	-	1	Melnick-Fraser syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.3
DANN	Benign	0.70
PhyloP100		-0.22
Mutation Taster		=99/1	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: rs1445398; hg19: chr8-72211295; COSMIC: COSV58172026;