8-71299202-C-T

Variant names:

• chr8-71299202-C-T
• rs201509408
• NM_000503.6:c.671G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000503.6(EYA1):​c.671G>A​(p.Gly224Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G224V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EYA1 NM_000503.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-71299202-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYA1	NM_000503.6	c.671G>A	p.Gly224Asp	missense_variant	Exon 9 of 18	ENST00000340726.8	NP_000494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYA1	ENST00000340726.8	c.671G>A	p.Gly224Asp	missense_variant	Exon 9 of 18	1	NM_000503.6	ENSP00000342626.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;T;.;.;.;T;T;.;.;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	.;.;.;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	1.4	L;L;L;.;.;.;L;L;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.38	N;.;N;N;N;N;.;.;.;.;.;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.16	T;.;T;T;T;T;.;.;.;.;.;T;T
Sift4G	Benign	0.28	T;.;T;T;T;T;.;.;.;.;.;T;T
Polyphen		0.95	P;P;P;.;P;P;P;P;.;.;.;.;.
Vest4		0.81
MutPred		0.21		Gain of stability (P = 0.0545);Gain of stability (P = 0.0545);Gain of stability (P = 0.0545);.;.;.;Gain of stability (P = 0.0545);Gain of stability (P = 0.0545);.;.;.;.;.;
MVP		0.90
MPC		0.78
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.31
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs201509408; hg19: chr8-72211437;