6-64813492-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001142800.2(EYS):c.3329C>G(p.Thr1110Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,550,532 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1110A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 4 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 1.61

Publications

4 publications found

Variant links:

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]

EYS Gene-Disease associations (from GenCC):

EYS-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
retinitis pigmentosa 25
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

EYS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018504202).

BP6

Variant 6-64813492-G-C is Benign according to our data. Variant chr6-64813492-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 554662.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142800.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	NM_001142800.2	MANE Select	c.3329C>G	p.Thr1110Ser	missense	Exon 22 of 43	NP_001136272.1
	EYS	NM_001292009.2		c.3329C>G	p.Thr1110Ser	missense	Exon 22 of 44	NP_001278938.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.3329C>G	p.Thr1110Ser	missense	Exon 22 of 43	ENSP00000424243.1
	EYS	ENST00000370621.7	TSL:1	c.3329C>G	p.Thr1110Ser	missense	Exon 22 of 44	ENSP00000359655.3

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00717

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

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:

0.0000147

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000514

AC:

AN:

155716

AF XY:

0.000327

show subpopulations

Gnomad AFR exome

AF:

0.00773

Gnomad AMR exome

AF:

0.000569

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000919

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000167

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.000210

AC:

293

AN:

1398414

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

116

AN XY:

689720

show subpopulations

African (AFR)

AF:

0.00739

AC:

233

AN:

31512

American (AMR)

AF:

0.000532

AC:

AN:

35692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25136

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35702

South Asian (SAS)

AF:

0.0000379

AC:

AN:

79198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49282

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00000464

AC:

AN:

1078228

Other (OTH)

AF:

0.000535

AC:

AN:

57974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00224

AC:

341

AN:

152118

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

169

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00768

AC:

319

AN:

41546

American (AMR)

AF:

0.00112

AC:

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67970

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000465

Hom.:

Bravo

AF:

0.00245

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000809

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Retinitis pigmentosa 25

Uncertain:2

Nov 07, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Sep 14, 2021

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

May 03, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26787102, 20333770)

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Optic atrophy

Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinitis pigmentosa

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.68

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.47

MutationAssessor

Benign

1.7

PhyloP100

1.6

PrimateAI

Benign

0.30

PROVEAN

Benign

-2.2

REVEL

Benign

0.25

Sift

Benign

0.11

Sift4G

Uncertain

0.023

Polyphen

0.38

Vest4

0.42

MutPred

0.84

Gain of glycosylation at T1110 (P = 0.0322)

MVP

0.31

MPC

0.049

ClinPred

0.030

GERP RS

2.3

Varity_R

0.074

gMVP

0.22

Mutation Taster

=52/48

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over