6-63720617-A-C

Variant names:

• chr6-63720617-A-C
• rs374161234
• NM_001142800.2:c.9414T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001142800.2(EYS):​c.9414T>G​(p.Asp3138Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000696 in 1,493,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000070 (0 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.02
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013729215).
• BP6: Variant 6-63720617-A-C is Benign according to our data. Variant chr6-63720617-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 964717.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.9414T>G	p.Asp3138Glu	missense_variant	Exon 43 of 43	ENST00000503581.6	NP_001136272.1
PHF3	NM_001370348.2	c.*6909A>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000262043.8	NP_001357277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.9414T>G	p.Asp3138Glu	missense_variant	Exon 43 of 43	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.9477T>G	p.Asp3159Glu	missense_variant	Exon 44 of 44	1		ENSP00000359655.3
PHF3	ENST00000262043.8	c.*6909A>C		3_prime_UTR_variant	Exon 16 of 16	5	NM_001370348.2	ENSP00000262043.4
PHF3	ENST00000505138.1	c.361+9255A>C		intron_variant	Intron 3 of 4	3		ENSP00000421417.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000218 AC: 25 AN: 114426 AF XY: 0.000238

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00203

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000701 AC: 94 AN: 1341268 Hom.: 0 Cov.: 28 AF XY: 0.0000746 AC XY: 49 AN XY: 657218

African (AFR) AF: 0.0000341 AC: 1 AN: 29330

American (AMR) AF: 0.00 AC: 0 AN: 26926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21674

East Asian (EAS) AF: 0.00153 AC: 54 AN: 35278

South Asian (SAS) AF: 0.000499 AC: 34 AN: 68114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47300

Middle Eastern (MID) AF: 0.000187 AC: 1 AN: 5360

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051718

Other (OTH) AF: 0.0000720 AC: 4 AN: 55568

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74454

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000831 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 3138 of the EYS protein (p.Asp3138Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 29641573). ClinVar contains an entry for this variant (Variation ID: 964717). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EYS protein function. 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. -

Mar 03, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Retinitis pigmentosa 25 Uncertain:1

Aug 05, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.042	.;T
Eigen	Benign	-0.017
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.2	.;L
PhyloP100		2.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.88	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.038	D;D
Polyphen		0.58	P;P
Vest4		0.30
MutPred		0.41		.;Gain of catalytic residue at D3159 (P = 0.087);
MVP		0.49
MPC		0.010
ClinPred		0.11	T
GERP RS		3.3
Varity_R		0.14
gMVP		0.16
Mutation Taster		=4/96	disease causing

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

Other links and lift over

dbSNP: rs374161234; hg19: chr6-64430513; COSMIC: COSV65481307;