6-63720628-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001142800.2(EYS):c.9403T>C(p.Tyr3135His) 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. 15/21 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. Y3135Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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 2 ACMG points.

• PM1: In a domain Laminin G-like 5 (size 190) in uniprot entity EYS_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) in NM_001142800.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16474983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.9403T>C	p.Tyr3135His	missense_variant	43/43	ENST00000503581.6
PHF3	NM_001370348.2	c.*6920A>G		3_prime_UTR_variant	16/16	ENST00000262043.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.9403T>C	p.Tyr3135His	missense_variant	43/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.9466T>C	p.Tyr3156His	missense_variant	44/44	1		P2
PHF3	ENST00000262043.8	c.*6920A>G		3_prime_UTR_variant	16/16	5	NM_001370348.2	P1
PHF3	ENST00000505138.1	c.363+9266A>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2023

The c.9403T>C (p.Y3135H) alteration is located in exon 43 (coding exon 40) of the EYS gene. This alteration results from a T to C substitution at nucleotide position 9403, causing the tyrosine (Y) at amino acid position 3135 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.20
Sift	Benign	0.11	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.16	B;B
Vest4		0.18
MutPred		0.49		.;Loss of phosphorylation at Y3156 (P = 0.0277);
MVP		0.40
MPC		0.0096
ClinPred		0.28	T
GERP RS		4.3
Varity_R		0.075
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-64430524;