6-138905131-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001286611.2(REPS1):​c.2324A>T​(p.Asp775Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

REPS1
NM_001286611.2 missense, splice_region

Scores

4
7
8
Splicing: ADA: 0.9425
1
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.28
Variant links:
Genes affected
REPS1 (HGNC:15578): (RALBP1 associated Eps domain containing 1) This gene encodes a signaling adaptor protein with two EH domains that interacts with proteins that participate in signaling, endocytosis and cytoskeletal changes. The encoded protein has been found in association with intersectin 1 and Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 when intersectin 1 was isolated from clathrin-coated pits. The encoded protein has also been shown to interact with amphiphysin, a cytoplasmic protein at the surface of synaptic vesicles. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.32015914).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
REPS1NM_001286611.2 linkc.2324A>T p.Asp775Val missense_variant, splice_region_variant Exon 20 of 20 ENST00000450536.7 NP_001273540.1 Q96D71-1B2R7D3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
REPS1ENST00000450536.7 linkc.2324A>T p.Asp775Val missense_variant, splice_region_variant Exon 20 of 20 1 NM_001286611.2 ENSP00000392065.2 Q96D71-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Feb 14, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 775 of the REPS1 protein (p.Asp775Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with REPS1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
T;.;T;.;.;T
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.32
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.81
N;.;.;.;.;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-4.0
D;D;D;D;D;D
REVEL
Uncertain
0.32
Sift
Benign
0.12
T;T;T;D;T;T
Sift4G
Benign
0.15
T;T;T;T;T;T
Polyphen
1.0
D;.;.;D;D;D
Vest4
0.70
MutPred
0.23
Gain of methylation at K774 (P = 0.0449);.;.;.;.;.;
MVP
0.34
MPC
0.41
ClinPred
0.98
D
GERP RS
6.2
Varity_R
0.46
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.94
dbscSNV1_RF
Pathogenic
0.85
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.

Other links and lift over

hg19: chr6-139226268; API