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GeneBe

6-138911287-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_001286611.2(REPS1):c.2056C>T(p.Pro686Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00158 in 1,604,920 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 7 hom. )

Consequence

REPS1
NM_001286611.2 missense

Scores

1
2
16

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.38
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 Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.00639382).
BP6
Variant 6-138911287-G-A is Benign according to our data. Variant chr6-138911287-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 638403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
REPS1NM_001286611.2 linkuse as main transcriptc.2056C>T p.Pro686Ser missense_variant 17/20 ENST00000450536.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
REPS1ENST00000450536.7 linkuse as main transcriptc.2056C>T p.Pro686Ser missense_variant 17/201 NM_001286611.2 P4Q96D71-1

Frequencies

GnomAD3 genomes
AF:
0.00117
AC:
178
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000265
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00118
Gnomad ASJ
AF:
0.0141
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000829
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00135
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00154
AC:
388
AN:
251194
Hom.:
1
AF XY:
0.00155
AC XY:
210
AN XY:
135758
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00142
Gnomad ASJ exome
AF:
0.0109
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000523
Gnomad FIN exome
AF:
0.000185
Gnomad NFE exome
AF:
0.00171
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.00162
AC:
2357
AN:
1452610
Hom.:
7
Cov.:
28
AF XY:
0.00167
AC XY:
1205
AN XY:
723480
show subpopulations
Gnomad4 AFR exome
AF:
0.000300
Gnomad4 AMR exome
AF:
0.00172
Gnomad4 ASJ exome
AF:
0.0113
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000512
Gnomad4 FIN exome
AF:
0.000150
Gnomad4 NFE exome
AF:
0.00160
Gnomad4 OTH exome
AF:
0.00231
GnomAD4 genome
AF:
0.00117
AC:
178
AN:
152310
Hom.:
0
Cov.:
32
AF XY:
0.00117
AC XY:
87
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000265
Gnomad4 AMR
AF:
0.00118
Gnomad4 ASJ
AF:
0.0141
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00135
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00216
Hom.:
2
Bravo
AF:
0.00145
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00221
AC:
19
ExAC
AF:
0.00134
AC:
163
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00273
EpiControl
AF:
0.00225

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 28, 2023- -
REPS1-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJul 16, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Neurodegeneration with brain iron accumulation 7 Benign:1
Likely benign, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesApr 27, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.30
Cadd
Benign
22
Dann
Uncertain
0.99
DEOGEN2
Benign
0.21
T;.;T;.;.
Eigen
Benign
-0.17
Eigen_PC
Benign
0.077
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.88
D;D;D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.0064
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.20
N;.;.;.;.
MutationTaster
Benign
0.98
D;D;D;D;D
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.4
N;N;N;N;N
REVEL
Benign
0.18
Sift
Benign
0.11
T;T;T;T;T
Sift4G
Benign
0.34
T;T;T;T;T
Polyphen
0.030
B;.;.;P;B
Vest4
0.48
MVP
0.21
MPC
0.25
ClinPred
0.019
T
GERP RS
5.3
Varity_R
0.080
gMVP
0.085

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144226246; hg19: chr6-139232424; API