rs4738118

Variant names:

• chr8-71216774-G-A
• rs4738118
• NM_000503.6:c.1278C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-71216774-G-A
• chr8-71216774-G-T

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.1278C>T​(p.Gly426Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 1,613,682 control chromosomes in the GnomAD database, including 28,388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G426G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (2843 hom., cov: 32)
  • Exomes 𝑓: 0.15 (25545 hom.)
• Consequence: EYA1 NM_000503.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.136
• Publications: 26 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

ENSG00000285579 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 8-71216774-G-A is Benign according to our data. Variant chr8-71216774-G-A is described in ClinVar as Benign. ClinVar VariationId is 48101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.136 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.638 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.1278C>T	p.Gly426Gly	synonymous	Exon 14 of 18	NP_000494.2
	EYA1	NM_001370333.1		c.1365C>T	p.Gly455Gly	synonymous	Exon 15 of 19	NP_001357262.1	A0A2R8Y6K4
	EYA1	NM_001370334.1		c.1278C>T	p.Gly426Gly	synonymous	Exon 16 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.1278C>T	p.Gly426Gly	synonymous	Exon 14 of 18	ENSP00000342626.3	Q99502-1
	EYA1	ENST00000388742.8	TSL:1	c.1278C>T	p.Gly426Gly	synonymous	Exon 13 of 17	ENSP00000373394.4	Q99502-1
	EYA1	ENST00000419131.6	TSL:1	c.1173C>T	p.Gly391Gly	synonymous	Exon 12 of 16	ENSP00000410176.1	Q99502-3

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23031 AN: 151934 Hom.: 2833 Cov.: 32

Gnomad AFR AF: 0.0921

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.656

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.149

GnomAD2 exomes AF: 0.219 AC: 54973 AN: 251276 AF XY: 0.215

Gnomad AFR exome AF: 0.0902

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.668

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.116

Gnomad OTH exome AF: 0.174

GnomAD4 exome AF: 0.149 AC: 218212 AN: 1461630 Hom.: 25545 Cov.: 33 AF XY: 0.153 AC XY: 110966 AN XY: 727138

African (AFR) AF: 0.0875 AC: 2930 AN: 33474

American (AMR) AF: 0.342 AC: 15274 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 3804 AN: 26134

East Asian (EAS) AF: 0.670 AC: 26582 AN: 39694

South Asian (SAS) AF: 0.310 AC: 26761 AN: 86258

European-Finnish (FIN) AF: 0.158 AC: 8419 AN: 53412

Middle Eastern (MID) AF: 0.117 AC: 673 AN: 5766

European-Non Finnish (NFE) AF: 0.111 AC: 123475 AN: 1111788

Other (OTH) AF: 0.170 AC: 10294 AN: 60390

GnomAD4 genome AF: 0.152 AC: 23074 AN: 152052 Hom.: 2843 Cov.: 32 AF XY: 0.161 AC XY: 11981 AN XY: 74318

African (AFR) AF: 0.0922 AC: 3825 AN: 41486

American (AMR) AF: 0.240 AC: 3665 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 480 AN: 3472

East Asian (EAS) AF: 0.656 AC: 3386 AN: 5158

South Asian (SAS) AF: 0.355 AC: 1706 AN: 4810

European-Finnish (FIN) AF: 0.161 AC: 1703 AN: 10576

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7721 AN: 67964

Other (OTH) AF: 0.157 AC: 332 AN: 2108

Alfa AF: 0.127 Hom.: 4208

Bravo AF: 0.155

Asia WGS AF: 0.513 AC: 1781 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Branchiootic syndrome 1 (1)
-	-	1	Melnick-Fraser syndrome (1)
-	-	1	Otofaciocervical syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.0
DANN	Benign	0.54
PhyloP100		-0.14
Mutation Taster		=92/8	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: rs4738118; hg19: chr8-72129009; COSMIC: COSV58162944;