rs117149407

Variant names:

• chr8-71199423-G-A
• rs117149407
• NM_000503.6:c.1699-3C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000503.6(EYA1):​c.1699-3C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0159 in 1,609,482 control chromosomes in the GnomAD database, including 269 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 33)
  • Exomes 𝑓: 0.016 (252 hom.)
• Consequence: EYA1 NM_000503.6 splice_region, intron
• Scores: Splicing: ADA: 0.002517
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.84
• Publications: 3 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

ENSG00000254031 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 8-71199423-G-A is Benign according to our data. Variant chr8-71199423-G-A is described in ClinVar as Benign. ClinVar VariationId is 48105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0117 (1779/152352) while in subpopulation AMR AF = 0.0216 (331/15306). AF 95% confidence interval is 0.0197. There are 17 homozygotes in GnomAd4. There are 848 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1779 AD gene.

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.1699-3C>T		splice_region intron	N/A	NP_000494.2
	EYA1	NM_001370333.1		c.1786-3C>T		splice_region intron	N/A	NP_001357262.1	A0A2R8Y6K4
	EYA1	NM_001370334.1		c.1699-3C>T		splice_region intron	N/A	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.1699-3C>T		splice_region intron	N/A	ENSP00000342626.3	Q99502-1
	EYA1	ENST00000388742.8	TSL:1	c.1699-3C>T		splice_region intron	N/A	ENSP00000373394.4	Q99502-1
	EYA1	ENST00000419131.6	TSL:1	c.1594-3C>T		splice_region intron	N/A	ENSP00000410176.1	Q99502-3

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1781 AN: 152234 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0217

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0165

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0151 AC: 3721 AN: 246102 AF XY: 0.0148

Gnomad AFR exome AF: 0.00323

Gnomad AMR exome AF: 0.0321

Gnomad ASJ exome AF: 0.00770

Gnomad EAS exome AF: 0.0000550

Gnomad FIN exome AF: 0.00682

Gnomad NFE exome AF: 0.0156

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0163 AC: 23811 AN: 1457130 Hom.: 252 Cov.: 31 AF XY: 0.0163 AC XY: 11791 AN XY: 724954

African (AFR) AF: 0.00260 AC: 87 AN: 33398

American (AMR) AF: 0.0298 AC: 1331 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00774 AC: 202 AN: 26102

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39614

South Asian (SAS) AF: 0.0191 AC: 1640 AN: 85884

European-Finnish (FIN) AF: 0.00818 AC: 428 AN: 52328

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5760

European-Non Finnish (NFE) AF: 0.0172 AC: 19120 AN: 1109168

Other (OTH) AF: 0.0162 AC: 973 AN: 60238

GnomAD4 genome AF: 0.0117 AC: 1779 AN: 152352 Hom.: 17 Cov.: 33 AF XY: 0.0114 AC XY: 848 AN XY: 74504

African (AFR) AF: 0.00286 AC: 119 AN: 41574

American (AMR) AF: 0.0216 AC: 331 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4832

European-Finnish (FIN) AF: 0.00631 AC: 67 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0166 AC: 1131 AN: 68038

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.0128 Hom.: 3

Bravo AF: 0.0132

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0156

EpiControl AF: 0.0141

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	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	-0.47
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		4.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.070		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: rs117149407; hg19: chr8-72111658;