17-1853171-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002945.5(RPA1):​c.343C>T​(p.Pro115Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,638 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RPA1
NM_002945.5 missense

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.19
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPA1NM_002945.5 linkc.343C>T p.Pro115Ser missense_variant Exon 5 of 17 ENST00000254719.10 NP_002936.1 P27694
RPA1NM_001355120.2 linkc.304C>T p.Pro102Ser missense_variant Exon 5 of 17 NP_001342049.1
RPA1NM_001355121.2 linkc.343C>T p.Pro115Ser missense_variant Exon 5 of 16 NP_001342050.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPA1ENST00000254719.10 linkc.343C>T p.Pro115Ser missense_variant Exon 5 of 17 1 NM_002945.5 ENSP00000254719.4 P27694
RPA1ENST00000570451.5 linkc.304C>T p.Pro102Ser missense_variant Exon 5 of 7 3 ENSP00000459788.1 I3L2M5
RPA1ENST00000571058.5 linkc.304C>T p.Pro102Ser missense_variant Exon 5 of 6 4 ENSP00000461733.1 I3L524
RPA1ENST00000571725.1 linkn.259C>T non_coding_transcript_exon_variant Exon 3 of 4 5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461638
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727150
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
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.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 23, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.343C>T (p.P115S) alteration is located in exon 5 (coding exon 5) of the RPA1 gene. This alteration results from a C to T substitution at nucleotide position 343, causing the proline (P) at amino acid position 115 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
T;T;D
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Uncertain
0.088
D
MetaRNN
Uncertain
0.68
D;D;D
MetaSVM
Benign
-0.30
T
MutationAssessor
Uncertain
2.7
.;.;M
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-6.3
.;.;D
REVEL
Uncertain
0.29
Sift
Uncertain
0.0040
.;.;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;.;D
Vest4
0.69
MutPred
0.40
.;.;Gain of sheet (P = 0.0477);
MVP
0.86
MPC
0.83
ClinPred
0.98
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.90
gMVP
0.87

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: rs1181652461; hg19: chr17-1756465; API