rs1554163965

Positions:

• chr6-63721512-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001142800.2(EYS):​c.8519A>G​(p.Glu2840Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E2840E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 3.36

Genes affected

EYS (HGNC:21555): (eyes shut homolog) The product of this gene contains multiple epidermal growth factor (EGF)-like and LamG domains. The protein is expressed in the photoreceptor layer of the retina, and the gene is mutated in autosomal recessive retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

PHF3 (HGNC:8921): (PHD finger protein 3) This gene encodes a member of a PHD finger-containing gene family. This gene may function as a transcription factor and may be involved in glioblastomas development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Laminin G-like 4 (size 178) in uniprot entity EYS_HUMAN there are 29 pathogenic changes around while only 5 benign (85%) in NM_001142800.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27859774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.8519A>G	p.Glu2840Gly	missense_variant	43/43	ENST00000503581.6
PHF3	NM_001370348.2	c.*7804T>C		3_prime_UTR_variant	16/16	ENST00000262043.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.8519A>G	p.Glu2840Gly	missense_variant	43/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.8582A>G	p.Glu2861Gly	missense_variant	44/44	1		P2
PHF3	ENST00000262043.8	c.*7804T>C		3_prime_UTR_variant	16/16	5	NM_001370348.2	P1
PHF3	ENST00000505138.1	c.363+10150T>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

Color vision defect;C0271385:Horizontal nystagmus;C0854723:Retinal dystrophy;C3665347:Visual impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Astigmatism;C0024440:Cystoid macular edema;C0476397:Abnormal electroretinogram;C0858618:Dyschromatopsia;C1862475:Abnormality of retinal pigmentation;C4021561:Electronegative electroretinogram;C4551715:Pigmentary retinopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Retinitis pigmentosa 25 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2016

This variant was classified as: Uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.64	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.26
Sift	Benign	0.057	T;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.13	B;B
Vest4		0.21
MutPred		0.76		.;Loss of stability (P = 0.0436);
MVP		0.40
MPC		0.042
ClinPred		0.67	D
GERP RS		2.2
Varity_R		0.14
gMVP		0.88

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: rs1554163965; hg19: chr6-64431408;