rs121909196

Variant names:

• chr8-71216733-C-A
• NM_000503.6:c.1319G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-71216733-C-A
• chr8-71216733-C-G
• chr8-71216733-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000503.6(EYA1):​c.1319G>T​(p.Arg440Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R440Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EYA1 NM_000503.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86

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]

ENSG00000285579 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-71216733-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA1	NM_000503.6	c.1319G>T	p.Arg440Leu	missense_variant	Exon 14 of 18	ENST00000340726.8	NP_000494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8	c.1319G>T	p.Arg440Leu	missense_variant	Exon 14 of 18	1	NM_000503.6	ENSP00000342626.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;D;.;.;.;D;D;.;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	.;.;.;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.9	M;M;M;.;.;.;M;M;.;.;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D;.;D;D;D;D;.;.;.;.;.;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0040	D;.;D;D;D;D;.;.;.;.;.;D;D
Sift4G	Uncertain	0.0050	D;.;D;D;D;D;.;.;.;.;.;D;D
Polyphen		0.67	P;P;P;.;P;P;P;P;.;.;.;.;.
Vest4		0.95
MutPred		0.82		Loss of MoRF binding (P = 0.061);Loss of MoRF binding (P = 0.061);Loss of MoRF binding (P = 0.061);.;.;.;Loss of MoRF binding (P = 0.061);Loss of MoRF binding (P = 0.061);.;.;.;.;.;
MVP		0.96
MPC		0.44
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.62
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-72128968;