rs398123576

Variant names:

• chr6-63721622-A-AT
• rs398123576
• NM_001142800.2:c.8408dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001292009.2(EYS):​c.8471dupA​(p.Asn2824LysfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000336 in 1,399,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N2824N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: EYS NM_001292009.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.788
• Publications: 2 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 16 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 146 pathogenic variants in the truncated region.
• PP5: Variant 6-63721622-A-AT is Pathogenic according to our data. Variant chr6-63721622-A-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 93622.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	NM_001142800.2	MANE Select	c.8408dupA	p.Asn2803LysfsTer9	frameshift	Exon 43 of 43	NP_001136272.1
	PHF3	NM_001370348.2	MANE Select	c.*7917dupT		3_prime_UTR	Exon 16 of 16	NP_001357277.1
	EYS	NM_001292009.2		c.8471dupA	p.Asn2824LysfsTer9	frameshift	Exon 44 of 44	NP_001278938.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.8408dupA	p.Asn2803LysfsTer9	frameshift	Exon 43 of 43	ENSP00000424243.1
	EYS	ENST00000370621.7	TSL:1	c.8471dupA	p.Asn2824LysfsTer9	frameshift	Exon 44 of 44	ENSP00000359655.3
	PHF3	ENST00000262043.8	TSL:5 MANE Select	c.*7917dupT		3_prime_UTR	Exon 16 of 16	ENSP00000262043.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000191 AC: 3 AN: 157218 AF XY: 0.0000120

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000328

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000336 AC: 47 AN: 1399074 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 19 AN XY: 690050

African (AFR) AF: 0.0000317 AC: 1 AN: 31582

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.00 AC: 0 AN: 79222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.0000417 AC: 45 AN: 1078588

Other (OTH) AF: 0.0000172 AC: 1 AN: 58042

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.79
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs398123576; hg19: chr6-64431518;