Genetic Variant NM_001142800.2:c.1155T>G (chr6-65402507-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001142800.2(EYS):c.1155T>G(p.Cys385Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,376,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. C385G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

EYS
NM_001142800.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.204

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

EYS-related retinopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
retinitis pigmentosa
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
retinitis pigmentosa 25
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

EYS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EYS	NM_001142800.2 link	c.1155T>G	p.Cys385Trp	missense_variant	Exon 7 of 43	ENST00000503581.6	NP_001136272.1	Q5T1H1-1
EYS	NM_001292009.2 link	c.1155T>G	p.Cys385Trp	missense_variant	Exon 7 of 44		NP_001278938.1	Q5T1H1-3
EYS	NM_001142801.2 link	c.1155T>G	p.Cys385Trp	missense_variant	Exon 7 of 12		NP_001136273.1	Q5T1H1-4
EYS	NM_198283.2 link	c.1155T>G	p.Cys385Trp	missense_variant	Exon 6 of 10		NP_938024.1	Q5T1H1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EYS	ENST00000503581.6 link	c.1155T>G	p.Cys385Trp	missense_variant	Exon 7 of 43	5	NM_001142800.2	ENSP00000424243.1	Q5T1H1-1
EYS	ENST00000370621.7 link	c.1155T>G	p.Cys385Trp	missense_variant	Exon 7 of 44	1		ENSP00000359655.3	Q5T1H1-3
EYS	ENST00000393380.6 link	c.1155T>G	p.Cys385Trp	missense_variant	Exon 7 of 12	1		ENSP00000377042.2	Q5T1H1-4
EYS	ENST00000342421.9 link	c.1155T>G	p.Cys385Trp	missense_variant	Exon 5 of 9	1		ENSP00000341818.5	Q5T1H1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.26e-7

AC:

AN:

1376844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689678

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31578

American (AMR)

AF:

0.00

AC:

AN:

44464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25472

East Asian (EAS)

AF:

0.00

AC:

AN:

39112

South Asian (SAS)

AF:

0.00

AC:

AN:

84258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

9.66e-7

AC:

AN:

1035642

Other (OTH)

AF:

0.00

AC:

AN:

57442

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

9.7

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.37

.;T;.;.

Eigen

Benign

-0.92

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.43

T;T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.6

M;M;M;M

PhyloP100

0.20

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-9.3

D;D;D;D

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

0.0010

B;.;.;B

Vest4

0.30

MutPred

0.84

Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);

MVP

0.33

MPC

0.0094

ClinPred

0.26

GERP RS

-0.87

Varity_R

0.37

gMVP

0.75

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over