rs144513453

Positions:

• chr6-63721602-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001142800.2(EYS):​c.8429C>T​(p.Thr2810Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,551,440 control chromosomes in the GnomAD database, including 8 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 0.0041 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (2 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.969

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 Benign. Variant got -11 ACMG points.

• PM1: In a domain Laminin G-like 4 (size 178) in uniprot entity EYS_HUMAN there are 29 pathogenic changes around while only 5 benign (85%) in NM_001142800.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.004781574).
• BP6: Variant 6-63721602-G-A is Benign according to our data. Variant chr6-63721602-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287296.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=6}. Variant chr6-63721602-G-A is described in Lovd as [Benign]. Variant chr6-63721602-G-A is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00411 (625/152186) while in subpopulation AFR AF= 0.0135 (562/41524). AF 95% confidence interval is 0.0126. There are 6 homozygotes in gnomad4. There are 322 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.8429C>T	p.Thr2810Ile	missense_variant	43/43	ENST00000503581.6
PHF3	NM_001370348.2	c.*7894G>A		3_prime_UTR_variant	16/16	ENST00000262043.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.8429C>T	p.Thr2810Ile	missense_variant	43/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.8492C>T	p.Thr2831Ile	missense_variant	44/44	1		P2
PHF3	ENST00000262043.8	c.*7894G>A		3_prime_UTR_variant	16/16	5	NM_001370348.2	P1
PHF3	ENST00000505138.1	c.363+10240G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 625 AN: 152068 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.000953 AC: 150 AN: 157414 Hom.: 0 AF XY: 0.000890 AC XY: 74 AN XY: 83106

Gnomad AFR exome AF: 0.0149

Gnomad AMR exome AF: 0.000445

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.00135

GnomAD4 exome AF: 0.000509 AC: 712 AN: 1399254 Hom.: 2 Cov.: 31 AF XY: 0.000480 AC XY: 331 AN XY: 690120

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000426

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00411 AC: 625 AN: 152186 Hom.: 6 Cov.: 32 AF XY: 0.00433 AC XY: 322 AN XY: 74400

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.000908 Hom.: 3

Bravo AF: 0.00459

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00795 AC: 11

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00136 AC: 34

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2020	This variant is associated with the following publications: (PMID: 20537394, 20237254) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	EYS: BP4, BS1, BS2 -

Retinitis pigmentosa 25 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 02, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2022	Variant summary: EYS c.8429C>T (p.Thr2810Ile) 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 0.00095 in 157414 control chromosomes, predominantly at a frequency of 0.015 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in EYS causing Retinitis Pigmentosa phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although reported in the literature among EYS variants unlikely to be pathogenic in a cohort of individuals with sporadic or autosomal recessive Retinitis Pigmentosa (example, Audo_2010), to our knowledge, no penetrant association of c.8429C>T in individuals affected with Retinitis Pigmentosa and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	.;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.12
Sift	Benign	0.078	T;T
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.010	B;B
Vest4		0.070
MVP		0.46
MPC		0.010
ClinPred		0.0052	T
GERP RS		2.8
Varity_R		0.064
gMVP		0.58

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: rs144513453; hg19: chr6-64431498;