6-63720626-A-T

Variant names:

• chr6-63720626-A-T
• rs137853190
• NM_001142800.2:c.9405T>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_001142800.2(EYS):​c.9405T>A​(p.Tyr3135*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,354,866 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y3135Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: EYS NM_001142800.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 2.41
• Publications: 12 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 5 pathogenic variants in the truncated region.
• PP5: Variant 6-63720626-A-T is Pathogenic according to our data. Variant chr6-63720626-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142800.2. 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.9405T>A	p.Tyr3135*	stop_gained	Exon 43 of 43	NP_001136272.1	Q5T1H1-1
	PHF3	NM_001370348.2	MANE Select	c.*6918A>T		3_prime_UTR	Exon 16 of 16	NP_001357277.1	Q92576-1
	EYS	NM_001292009.2		c.9468T>A	p.Tyr3156*	stop_gained	Exon 44 of 44	NP_001278938.1	Q5T1H1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EYS	ENST00000503581.6	TSL:5 MANE Select	c.9405T>A	p.Tyr3135*	stop_gained	Exon 43 of 43	ENSP00000424243.1	Q5T1H1-1
	EYS	ENST00000370621.7	TSL:1	c.9468T>A	p.Tyr3156*	stop_gained	Exon 44 of 44	ENSP00000359655.3	Q5T1H1-3
	PHF3	ENST00000262043.8	TSL:5 MANE Select	c.*6918A>T		3_prime_UTR	Exon 16 of 16	ENSP00000262043.4	Q92576-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000161 AC: 2 AN: 124588 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000284

GnomAD4 exome AF: 0.0000140 AC: 19 AN: 1354866 Hom.: 0 Cov.: 28 AF XY: 0.0000180 AC XY: 12 AN XY: 665040

African (AFR) AF: 0.00 AC: 0 AN: 29778

American (AMR) AF: 0.000206 AC: 6 AN: 29150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22502

East Asian (EAS) AF: 0.00 AC: 0 AN: 35348

South Asian (SAS) AF: 0.00 AC: 0 AN: 70488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47828

Middle Eastern (MID) AF: 0.000184 AC: 1 AN: 5448

European-Non Finnish (NFE) AF: 0.0000113 AC: 12 AN: 1058164

Other (OTH) AF: 0.00 AC: 0 AN: 56160

GnomAD4 genome Cov.: 32

Alfa AF: 0.000166 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Retinitis pigmentosa 25 (7)
5	-	-	not provided (5)
2	-	-	Retinal dystrophy (2)
1	-	-	EYS-related disorder (1)
1	-	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		2.4
Vest4		0.54
GERP RS		3.4
Mutation Taster		=6/194	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: rs137853190; hg19: chr6-64430522;