6-63720752-AC-A

Variant names:

• chr6-63720752-AC-A
• rs869312188
• NM_001142800.2:c.9278delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000503581.6(EYS):​c.9278delG​(p.Gly3093ValfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G3093G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EYS ENST00000503581.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.24
• 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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 35 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-63720752-AC-A is Pathogenic according to our data. Variant chr6-63720752-AC-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3241494.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000503581.6. 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.9278delG	p.Gly3093ValfsTer4	frameshift	Exon 43 of 43	NP_001136272.1
	PHF3	NM_001370348.2	MANE Select	c.*7046delC		3_prime_UTR	Exon 16 of 16	NP_001357277.1
	EYS	NM_001292009.2		c.9341delG	p.Gly3114ValfsTer4	frameshift	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.9278delG	p.Gly3093ValfsTer4	frameshift	Exon 43 of 43	ENSP00000424243.1
	EYS	ENST00000370621.7	TSL:1	c.9341delG	p.Gly3114ValfsTer4	frameshift	Exon 44 of 44	ENSP00000359655.3
	PHF3	ENST00000262043.8	TSL:5 MANE Select	c.*7046delC		3_prime_UTR	Exon 16 of 16	ENSP00000262043.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Retinitis pigmentosa 25 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2

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: rs869312188; hg19: chr6-64430648;