rs200345478

Variant names:

• chr8-71216952-C-A
• rs200345478
• NM_000503.6:c.1199+13G>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.1199+13G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,612,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: EYA1 NM_000503.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.732
• Publications: 0 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=-0.86).
• BP6: Variant 8-71216952-C-A is Benign according to our data. Variant chr8-71216952-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0009 (137/152304) while in subpopulation AFR AF = 0.00315 (131/41578). AF 95% confidence interval is 0.00271. There are 0 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 137 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA1	NM_000503.6	MANE Select	c.1199+13G>T		intron	N/A	NP_000494.2
	EYA1	NM_001370333.1		c.1286+13G>T		intron	N/A	NP_001357262.1
	EYA1	NM_001370334.1		c.1199+13G>T		intron	N/A	NP_001357263.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYA1	ENST00000340726.8	TSL:1 MANE Select	c.1199+13G>T		intron	N/A	ENSP00000342626.3
	EYA1	ENST00000388742.8	TSL:1	c.1199+13G>T		intron	N/A	ENSP00000373394.4
	EYA1	ENST00000419131.6	TSL:1	c.1094+13G>T		intron	N/A	ENSP00000410176.1

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000271 AC: 68 AN: 251204 AF XY: 0.000192

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.000260

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: 0.000163

GnomAD4 exome AF: 0.0000993 AC: 145 AN: 1460676 Hom.: 0 Cov.: 31 AF XY: 0.0000771 AC XY: 56 AN XY: 726722

African (AFR) AF: 0.00341 AC: 114 AN: 33448

American (AMR) AF: 0.000246 AC: 11 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110934

Other (OTH) AF: 0.000298 AC: 18 AN: 60354

GnomAD4 genome AF: 0.000900 AC: 137 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000806 AC XY: 60 AN XY: 74484

African (AFR) AF: 0.00315 AC: 131 AN: 41578

American (AMR) AF: 0.000196 AC: 3 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000975

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.37
PhyloP100		-0.73
Mutation Taster		=100/0	polymorphism

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: rs200345478; hg19: chr8-72129187;