17-1872485-C-T

Variant summary

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

The NM_002945.5(RPA1):​c.413C>T​(p.Ala138Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RPA1
NM_002945.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.205
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.413C>T p.Ala138Val missense_variant Exon 6 of 17 ENST00000254719.10 NP_002936.1 P27694
RPA1NM_001355120.2 linkc.374C>T p.Ala125Val missense_variant Exon 6 of 17 NP_001342049.1
RPA1NM_001355121.2 linkc.413C>T p.Ala138Val missense_variant Exon 6 of 16 NP_001342050.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPA1ENST00000254719.10 linkc.413C>T p.Ala138Val missense_variant Exon 6 of 17 1 NM_002945.5 ENSP00000254719.4 P27694
RPA1ENST00000570451.5 linkc.374C>T p.Ala125Val missense_variant Exon 6 of 7 3 ENSP00000459788.1 I3L2M5
RPA1ENST00000573924.1 linkn.137C>T non_coding_transcript_exon_variant Exon 2 of 6 4
RPA1ENST00000571058.5 linkc.*2C>T downstream_gene_variant 4 ENSP00000461733.1 I3L524

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000479
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461788
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727186
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152142
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000479
Bravo
AF:
0.0000264

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jan 17, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.413C>T (p.A138V) alteration is located in exon 6 (coding exon 6) of the RPA1 gene. This alteration results from a C to T substitution at nucleotide position 413, causing the alanine (A) at amino acid position 138 to be replaced by a valine (V). 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
Benign
0.071
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
9.7
DANN
Benign
0.86
DEOGEN2
Benign
0.018
T;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.47
T;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.054
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.69
.;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
0.060
.;N
REVEL
Benign
0.021
Sift
Benign
0.30
.;T
Sift4G
Benign
0.20
T;T
Polyphen
0.0
.;B
Vest4
0.14
MutPred
0.12
.;Loss of glycosylation at P136 (P = 0.1027);
MVP
0.42
MPC
0.22
ClinPred
0.061
T
GERP RS
0.36
Varity_R
0.047
gMVP
0.29

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.22
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.22
Position offset: 41

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: rs1913411066; hg19: chr17-1775779; API