rs146413074

chr6-64593299-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001142800.2(EYS):c.3695T>C(p.Ile1232Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000069 in 1,549,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1232F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -1.53

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.008581251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.3695T>C	p.Ile1232Thr	missense_variant	25/43	ENST00000503581.6
EYS	NM_001292009.2	c.3695T>C	p.Ile1232Thr	missense_variant	25/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.3695T>C	p.Ile1232Thr	missense_variant	25/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.3695T>C	p.Ile1232Thr	missense_variant	25/44	1		P2
EYS	ENST00000330816.5	n.316T>C		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000772 AC: 12 AN: 155446 Hom.: 0 AF XY: 0.0000728 AC XY: 6 AN XY: 82422

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.000371

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000443

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000594 AC: 83 AN: 1397382 Hom.: 0 Cov.: 30 AF XY: 0.0000638 AC XY: 44 AN XY: 689228

Gnomad4 AFR exome AF: 0.000635

Gnomad4 AMR exome AF: 0.000394

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000380

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000190

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74440

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000662 Hom.: 0

Bravo AF: 0.000140

ExAC AF: 0.0000408 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 25 Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 31, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 08, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 20, 2024

Variant summary: EYS c.3695T>C (p.Ile1232Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 155446 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in EYS causing Retinitis Pigmentosa (7.7e-05 vs 0.0034), allowing no conclusion about variant significance. c.3695T>C has been reported in the literature in individuals affected with Retinitis Pigmentosa (examples: Gonzlez-del Pozo_2011, Messchaert_2018, Xu_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22164218, 29159838, 34178978). ClinVar contains an entry for this variant (Variation ID: 551910). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1232 of the EYS protein (p.Ile1232Thr). This variant is present in population databases (rs146413074, gnomAD 0.04%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 22164218, 29159838). ClinVar contains an entry for this variant (Variation ID: 551910). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Ile232 amino acid residue in EYS. Other variant(s) that disrupt this residue have been observed in individuals with EYS-related conditions (PMID: 20333770), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	0.0080
Dann	Benign	0.84
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.20
Sift	Benign	0.52	T;T
Sift4G	Uncertain	0.060	T;T
Polyphen		0.0010	B;B
Vest4		0.034
MVP		0.076
MPC		0.0095
ClinPred		0.0070	T
GERP RS		-9.2
Varity_R		0.043
gMVP		0.23

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: rs146413074; hg19: chr6-65303192;