17-1844682-G-A
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_002945.5(RPA1):c.268G>A(p.Gly90Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,609,720 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
RPA1
NM_002945.5 missense
NM_002945.5 missense
Scores
5
6
4
Clinical Significance
Conservation
PhyloP100: 6.58
Genes affected
RPA1 (HGNC:10289): (replication protein A1) This gene encodes the largest subunit of the heterotrimeric Replication Protein A (RPA) complex, which binds to single-stranded DNA (ssDNA), forming a nucleoprotein complex that plays an important role in DNA metabolism, being involved in DNA replication, repair, recombination, telomere maintenance, and co-ordinating the cellular response to DNA damage through activation of the ataxia telangiectasia and Rad3-related protein (ATR) kinase. The nucleoprotein complex protects the single-stranded DNA from nucleases, prevents formation of secondary structures that would interfere with repair, and co-ordinates the recruitment and departure of different genome maintenance factors. This subunit contains four oligonucleotide/oligosaccharide-binding (OB) domains, though the majority of ssDNA binding occurs in two of these domains. The heterotrimeric complex has two different modes of ssDNA binding, a low-affinity and high-affinity mode, determined by which ssDNA binding domains are utilized. The different binding modes differ in the length of DNA bound and in the proteins with which it interacts, thereby playing a role in regulating different genomic maintenance pathways. [provided by RefSeq, Sep 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
BS2
?
High AC in GnomAd at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPA1 | NM_002945.5 | c.268G>A | p.Gly90Arg | missense_variant | 4/17 | ENST00000254719.10 | |
RPA1 | NM_001355120.2 | c.229G>A | p.Gly77Arg | missense_variant | 4/17 | ||
RPA1 | NM_001355121.2 | c.268G>A | p.Gly90Arg | missense_variant | 4/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPA1 | ENST00000254719.10 | c.268G>A | p.Gly90Arg | missense_variant | 4/17 | 1 | NM_002945.5 | P1 | |
RPA1 | ENST00000570451.5 | c.229G>A | p.Gly77Arg | missense_variant | 4/7 | 3 | |||
RPA1 | ENST00000571058.5 | c.229G>A | p.Gly77Arg | missense_variant | 4/6 | 4 | |||
RPA1 | ENST00000571725.1 | n.184G>A | non_coding_transcript_exon_variant | 2/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152166Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000206 AC: 3AN: 1457554Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2AN XY: 725104
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152166Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74338
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 07, 2021 | The c.268G>A (p.G90R) alteration is located in exon 4 (coding exon 4) of the RPA1 gene. This alteration results from a G to A substitution at nucleotide position 268, causing the glycine (G) at amino acid position 90 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Benign
T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Sift4G
Uncertain
D;D;T
Polyphen
1.0
.;.;D
Vest4
0.82
MutPred
0.59
.;.;Gain of MoRF binding (P = 0.0448);
MVP
MPC
0.82
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at