rs1554163993

Variant names:

• chr6-63721663-T-C
• rs1554163993
• NM_001142800.2:c.8368A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_001292009.2(EYS):​c.8431A>G​(p.Arg2811Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000858 in 1,399,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: EYS NM_001292009.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:2
• Conservation: PhyloP100: 3.21
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 6-63721663-T-C is Pathogenic according to our data. Variant chr6-63721663-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001292009.2. 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.8368A>G	p.Arg2790Gly	missense	Exon 43 of 43	NP_001136272.1
	PHF3	NM_001370348.2	MANE Select	c.*7955T>C		3_prime_UTR	Exon 16 of 16	NP_001357277.1
	EYS	NM_001292009.2		c.8431A>G	p.Arg2811Gly	missense	Exon 44 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.8368A>G	p.Arg2790Gly	missense	Exon 43 of 43	ENSP00000424243.1
	EYS	ENST00000370621.7	TSL:1	c.8431A>G	p.Arg2811Gly	missense	Exon 44 of 44	ENSP00000359655.3
	PHF3	ENST00000262043.8	TSL:5 MANE Select	c.*7955T>C		3_prime_UTR	Exon 16 of 16	ENSP00000262043.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000858 AC: 12 AN: 1399230 Hom.: 0 Cov.: 31 AF XY: 0.0000116 AC XY: 8 AN XY: 690110

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.0000280 AC: 1 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35722

South Asian (SAS) AF: 0.00 AC: 0 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1078786

Other (OTH) AF: 0.00 AC: 0 AN: 58022

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Retinitis pigmentosa (2)
-	2	-	Retinitis pigmentosa 25 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		3.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.72
Sift	Benign	0.095	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.69		Gain of catalytic residue at V2812 (P = 0.0457)
MVP		0.57
MPC		0.060
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.36
gMVP		0.85
Mutation Taster		=1/99	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: rs1554163993; hg19: chr6-64431559;