NM_000503.6:c.124+3061G>C

Variant names:

• chr8-71351721-C-G
• rs2218488
• NM_000503.6:c.124+3061G>C

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_000503.6(EYA1):c.124+3061G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EYA1 NM_000503.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 16 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, STRONG, SUPPORTIVE Submitted by: ClinGen, PanelApp Australia, Orphanet
• branchiootorenal syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• branchiootic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000503.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	EYA1 NM_000503.6	MANE Select	c.124+3061G>C	intron	Intron 3 of 17	Prot: NP_000494.2
	EYA1 NM_001370333.1		c.211+3061G>C	intron	Intron 4 of 18	Prot: NP_001357262.1 UniProt:
	EYA1 NM_001370334.1		c.124+3061G>C	intron	Intron 5 of 19	Prot: NP_001357263.1 UniProt:

EYA1 NM_000503.6

MANE Select

HGVSc / HGVSpc.124+3061G>C

Exon rankIntron 3 of 17

intron

Prot: NP_000494.2

EYA1 NM_001370333.1

HGVSc / HGVSpc.211+3061G>C

Exon rankIntron 4 of 18

intron

Prot: NP_001357262.1UniProt: A0A2R8Y6K4

EYA1 NM_001370334.1

HGVSc / HGVSpc.124+3061G>C

Exon rankIntron 5 of 19

intron

Prot: NP_001357263.1UniProt: Q99502-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	EYA1 ENST00000340726.8	TSL:1MANE Select	c.124+3061G>C	intron	Intron 3 of 17	Prot: ENSP00000342626.3 UniProt:
	EYA1 ENST00000388742.8	TSL:1	c.124+3061G>C	intron	Intron 2 of 16	Prot: ENSP00000373394.4 UniProt:
	EYA1 ENST00000419131.6	TSL:1	c.124+3061G>C	intron	Intron 2 of 15	Prot: ENSP00000410176.1 UniProt:

EYA1 ENST00000340726.8

TSL:1MANE Select

HGVSc / HGVSpc.124+3061G>C

Exon rankIntron 3 of 17

intron

Prot: ENSP00000342626.3UniProt: Q99502-1

EYA1 ENST00000388742.8

TSL:1

HGVSc / HGVSpc.124+3061G>C

Exon rankIntron 2 of 16

intron

Prot: ENSP00000373394.4UniProt: Q99502-1

EYA1 ENST00000419131.6

TSL:1

HGVSc / HGVSpc.124+3061G>C

Exon rankIntron 2 of 15

intron

Prot: ENSP00000410176.1UniProt: Q99502-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
TOPMed (Bravo) Warning	AF: 0.00537	AC:1421	Hom:1	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:241624	AN:701324	Cov:

Showing 4 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.73
GPN-Star LLR	N/A	0.27
GPN-Star score	N/A	-0.27
PhyloP100	Benign	1.2

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2218488;

hg19: chr8-72263956;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar