rs201819948

Positions:

• chr6-64886718-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001142800.2(EYS):​c.2971C>T​(p.Leu991Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,545,658 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: EYS NM_001142800.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: -0.414

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04381132).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EYS	NM_001142800.2	c.2971C>T	p.Leu991Phe	missense_variant	19/43	ENST00000503581.6
EYS	NM_001292009.2	c.2971C>T	p.Leu991Phe	missense_variant	19/44

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EYS	ENST00000503581.6	c.2971C>T	p.Leu991Phe	missense_variant	19/43	5	NM_001142800.2	A2
EYS	ENST00000370621.7	c.2971C>T	p.Leu991Phe	missense_variant	19/44	1		P2

Frequencies

GnomAD3 genomes AF: 0.000244 AC: 37 AN: 151880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000407 AC: 62 AN: 152446 Hom.: 0 AF XY: 0.000469 AC XY: 38 AN XY: 80956

Gnomad AFR exome AF: 0.000133

Gnomad AMR exome AF: 0.000209

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000579

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000341

Gnomad OTH exome AF: 0.000473

GnomAD4 exome AF: 0.000388 AC: 541 AN: 1393662 Hom.: 2 Cov.: 30 AF XY: 0.000397 AC XY: 273 AN XY: 687398

Gnomad4 AFR exome AF: 0.000320

Gnomad4 AMR exome AF: 0.000285

Gnomad4 ASJ exome AF: 0.00232

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000573

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.000286

Gnomad4 OTH exome AF: 0.000901

GnomAD4 genome AF: 0.000237 AC: 36 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000459 Hom.: 0

Bravo AF: 0.000264

ExAC AF: 0.000371 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa 25 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Feb 04, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 30, 2017	- -

not provided Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 23, 2022

Variant summary: EYS c.2971C>T (p.Leu991Phe) results in a non-conservative amino acid change located in the EGF-like calcium-binding domain of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 152446 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in EYS causing Retinitis Pigmentosa (0.00041 vs 0.0034), allowing no conclusion about variant significance. c.2971C>T has been reported in the literature in individuals affected with Retinitis Pigmentosa. These reports do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. This variant has been found to be in-cis with c.32dup/p.(Met12Aspfs*14) in one patient (Colombo_2021). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=5). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.1
DANN	Uncertain	0.99
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.17
Sift	Benign	0.056	T;T
Sift4G	Benign	0.097	T;T
Polyphen		0.36	B;.
Vest4		0.34
MVP		0.24
MPC		0.0098
ClinPred		0.0067	T
GERP RS		-0.11
Varity_R		0.061
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs201819948; hg19: chr6-65596611;