dbSNP rs111991705: EYS:p.Ala2808Pro (chr6-63721609-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_001142800.2(EYS):c.8422G>C(p.Ala2808Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2808T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.408

Variant links:

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]

EYS links:

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]

PHF3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a domain Laminin G-like 4 (size 178) in uniprot entity EYS_HUMAN there are 22 pathogenic changes around while only 1 benign (96%) in NM_001142800.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-63721609-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.26813066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.8422G>C	p.Ala2808Pro	missense_variant	Exon 43 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
PHF3	NM_001370348.2 link	c.*7901C>G		3_prime_UTR_variant	Exon 16 of 16	ENST00000262043.8	NP_001357277.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EYS	ENST00000503581.6 link	c.8422G>C	p.Ala2808Pro	missense_variant	Exon 43 of 43	5	NM_001142800.2	ENSP00000424243.1	Q5T1H1-1
EYS	ENST00000370621.7 link	c.8485G>C	p.Ala2829Pro	missense_variant	Exon 44 of 44	1		ENSP00000359655.3	Q5T1H1-3
PHF3	ENST00000262043.8 link	c.*7901C>G		3_prime_UTR_variant	Exon 16 of 16	5	NM_001370348.2	ENSP00000262043.4	Q92576-1
PHF3	ENST00000505138.1 link	c.361+10247C>G		intron_variant	Intron 3 of 4	3		ENSP00000421417.1	H0Y8L0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399050

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

.;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.50

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.4

.;M

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.23

Sift

Benign

0.064

T;T

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;D

Vest4

0.17

MutPred

0.55

.;Gain of glycosylation at T2826 (P = 0.0704);

MVP

0.44

MPC

0.021

ClinPred

0.78

GERP RS

2.9

Varity_R

0.14

gMVP

0.74

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over