rs372286227

Variant names:

• chr8-71211271-T-C
• rs372286227
• NM_000503.6:c.1598-15A>G

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.1598-15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000474 in 1,534,842 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (6 hom.)
• Consequence: EYA1 NM_000503.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.185
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-71211271-T-C is Benign according to our data. Variant chr8-71211271-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000328 (50/152352) while in subpopulation SAS AF = 0.0103 (50/4834). AF 95% confidence interval is 0.00806. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 50 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.1598-15A>G		intron	N/A	NP_000494.2
	EYA1	NM_001370333.1		c.1685-15A>G		intron	N/A	NP_001357262.1	A0A2R8Y6K4
	EYA1	NM_001370334.1		c.1598-15A>G		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.1598-15A>G		intron	N/A	ENSP00000342626.3	Q99502-1
	EYA1	ENST00000388742.8	TSL:1	c.1598-15A>G		intron	N/A	ENSP00000373394.4	Q99502-1
	EYA1	ENST00000419131.6	TSL:1	c.1493-15A>G		intron	N/A	ENSP00000410176.1	Q99502-3

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0105

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000975 AC: 244 AN: 250318 AF XY: 0.00129

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.000490 AC: 677 AN: 1382490 Hom.: 6 Cov.: 23 AF XY: 0.000694 AC XY: 481 AN XY: 692950

African (AFR) AF: 0.0000314 AC: 1 AN: 31886

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25636

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39300

South Asian (SAS) AF: 0.00755 AC: 639 AN: 84660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.00000384 AC: 4 AN: 1040556

Other (OTH) AF: 0.000555 AC: 32 AN: 57694

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74504

African (AFR) AF: 0.00 AC: 0 AN: 41598

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0103 AC: 50 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000347 Hom.: 1

Bravo AF: 0.000110

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Branchiootic syndrome 1 (1)
-	-	1	Branchiootic syndrome 1;C3714941:Otofaciocervical syndrome 1;C4551702:Branchiootorenal 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	-0.78
CADD	Benign	2.4
DANN	Benign	0.55
PhyloP100		0.18
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: rs372286227; hg19: chr8-72123506;