6-63721609-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001142800.2(EYS):c.8422G>A(p.Ala2808Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,551,202 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0070 ( 15 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 49 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 0.408

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 links:

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]

PHF3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a domain Laminin G-like 4 (size 178) in uniprot entity EYS_HUMAN there are 22 pathogenic changes around while only 1 benign (96%) in NM_001142800.2

BP4

Computational evidence support a benign effect (MetaRNN=0.0044193566).

BP6

Variant 6-63721609-C-T is Benign according to our data. Variant chr6-63721609-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252538.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=2, Uncertain_significance=1}. Variant chr6-63721609-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00702 (1068/152162) while in subpopulation SAS AF= 0.0235 (113/4816). AF 95% confidence interval is 0.02. There are 15 homozygotes in gnomad4. There are 550 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.8422G>A	p.Ala2808Thr	missense_variant	Exon 43 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
PHF3	NM_001370348.2 link	c.*7901C>T		3_prime_UTR_variant	Exon 16 of 16	ENST00000262043.8	NP_001357277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EYS	ENST00000503581.6 link	c.8422G>A	p.Ala2808Thr	missense_variant	Exon 43 of 43	5	NM_001142800.2	ENSP00000424243.1	Q5T1H1-1
EYS	ENST00000370621.7 link	c.8485G>A	p.Ala2829Thr	missense_variant	Exon 44 of 44	1		ENSP00000359655.3	Q5T1H1-3
PHF3	ENST00000262043.8 link	c.*7901C>T		3_prime_UTR_variant	Exon 16 of 16	5	NM_001370348.2	ENSP00000262043.4	Q92576-1
PHF3	ENST00000505138.1 link	c.361+10247C>T		intron_variant	Intron 3 of 4	3		ENSP00000421417.1	H0Y8L0

Frequencies

GnomAD3 genomes

AF:

0.00701

AC:

1066

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0206

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00847

Gnomad SAS

AF:

0.0232

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00510

AC:

802

AN:

157312

Hom.:

AF XY:

0.00591

AC XY:

491

AN XY:

83112

show subpopulations

Gnomad AFR exome

AF:

0.0186

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00176

Gnomad EAS exome

AF:

0.0109

Gnomad SAS exome

AF:

0.0203

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000164

Gnomad OTH exome

AF:

0.00316

GnomAD4 exome

AF:

0.00200

AC:

2792

AN:

1399040

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

1702

AN XY:

690046

show subpopulations

Gnomad4 AFR exome

AF:

0.0209

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00139

Gnomad4 EAS exome

AF:

0.00481

Gnomad4 SAS exome

AF:

0.0197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000723

Gnomad4 OTH exome

AF:

0.00348

GnomAD4 genome

AF:

0.00702

AC:

1068

AN:

152162

Hom.:

Cov.:

AF XY:

0.00739

AC XY:

550

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0205

Gnomad4 AMR

AF:

0.00223

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00849

Gnomad4 SAS

AF:

0.0235

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.00159

Hom.:

Bravo

AF:

0.00720

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0210

AC:

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.00890

AC:

222

Asia WGS

AF:

0.0180

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 18, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 24, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 25

Benign:3

Jun 19, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa

Uncertain:1Benign: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. -

Dec 27, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Jul 26, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

.;T

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.54

T;T

MetaRNN

Benign

0.0044

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

.;L

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.64

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.027

D;T

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.59

P;P

Vest4

0.36

MVP

0.34

MPC

0.010

ClinPred

0.0061

GERP RS

2.9

Varity_R

0.038

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over