rs1554163939

Positions:

• chr6-63721413-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001142800.2(EYS):​c.8618A>G​(p.Asp2873Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000572 in 1,399,434 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.28

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 4 ACMG points.

• PM1: In a disulfide_bond (size 27) in uniprot entity EYS_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001142800.2
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EYS	NM_001142800.2	c.8618A>G	p.Asp2873Gly	missense_variant	43/43	ENST00000503581.6	NP_001136272.1
PHF3	NM_001370348.2	c.*7705T>C		3_prime_UTR_variant	16/16	ENST00000262043.8	NP_001357277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.8618A>G	p.Asp2873Gly	missense_variant	43/43	5	NM_001142800.2	ENSP00000424243	A2
EYS	ENST00000370621.7	c.8681A>G	p.Asp2894Gly	missense_variant	44/44	1		ENSP00000359655	P2
PHF3	ENST00000262043.8	c.*7705T>C		3_prime_UTR_variant	16/16	5	NM_001370348.2	ENSP00000262043	P1
PHF3	ENST00000505138.1	c.363+10051T>C		intron_variant		3		ENSP00000421417

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000572 AC: 8 AN: 1399434 Hom.: 0 Cov.: 32 AF XY: 0.00000724 AC XY: 5 AN XY: 690206

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000741

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EYS protein function. ClinVar contains an entry for this variant (Variation ID: 438210). This missense change has been observed in individual(s) with inherited retinal dystrohy (PMID: 28041643). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2873 of the EYS protein (p.Asp2873Gly). -

Retinitis pigmentosa 25 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Nov 08, 2017

- -

Retinitis pigmentosa Uncertain:1

Uncertain significance, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.2	.;M
MutationTaster	Benign	0.83	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.52
MutPred		0.42		.;Gain of disorder (P = 0.1764);
MVP		0.52
MPC		0.055
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.39
gMVP		0.92

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: rs1554163939; hg19: chr6-64431309;