6-64813377-C-T

Variant names:

• chr6-64813377-C-T
• rs373441420
• NM_001142800.2:c.3443+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001142800.2(EYS):​c.3443+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000649 in 1,386,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: EYS NM_001142800.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.76

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 10, offset of 22, new splice context is: caaGTaagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-64813377-C-T is Pathogenic according to our data. Variant chr6-64813377-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1069772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-64813377-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2	c.3443+1G>A		splice_donor_variant, intron_variant	Intron 22 of 42	ENST00000503581.6	NP_001136272.1
EYS	NM_001292009.2	c.3443+1G>A		splice_donor_variant, intron_variant	Intron 22 of 43		NP_001278938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EYS	ENST00000503581.6	c.3443+1G>A		splice_donor_variant, intron_variant	Intron 22 of 42	5	NM_001142800.2	ENSP00000424243.1
EYS	ENST00000370621.7	c.3443+1G>A		splice_donor_variant, intron_variant	Intron 22 of 43	1		ENSP00000359655.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000137 AC: 2 AN: 146414 Hom.: 0 AF XY: 0.0000128 AC XY: 1 AN XY: 77882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000899

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000649 AC: 9 AN: 1386652 Hom.: 0 Cov.: 30 AF XY: 0.00000732 AC XY: 5 AN XY: 683394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000589

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000466

Gnomad4 OTH exome AF: 0.0000348

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 25 Pathogenic:2

Dec 28, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 22 of the EYS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EYS are known to be pathogenic (PMID: 18836446, 20333770). This variant is present in population databases (no rsID available, gnomAD 0.005%). Disruption of this splice site has been observed in individuals with retinitis pigmentosa (PMID: 20237254, 25097241, 26667666). ClinVar contains an entry for this variant (Variation ID: 1069772). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.88	D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.98		Position offset: -21
DS_DL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs373441420; hg19: chr6-65523270;