chr17-1872510-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002945.5(RPA1):​c.438T>G​(p.Asn146Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RPA1
NM_002945.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.260
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12515765).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RPA1NM_002945.5 linkuse as main transcriptc.438T>G p.Asn146Lys missense_variant 6/17 ENST00000254719.10 NP_002936.1
RPA1NM_001355120.2 linkuse as main transcriptc.399T>G p.Asn133Lys missense_variant 6/17 NP_001342049.1
RPA1NM_001355121.2 linkuse as main transcriptc.438T>G p.Asn146Lys missense_variant 6/16 NP_001342050.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RPA1ENST00000254719.10 linkuse as main transcriptc.438T>G p.Asn146Lys missense_variant 6/171 NM_002945.5 ENSP00000254719 P1
RPA1ENST00000570451.5 linkuse as main transcriptc.399T>G p.Asn133Lys missense_variant 6/73 ENSP00000459788
RPA1ENST00000573924.1 linkuse as main transcriptn.162T>G non_coding_transcript_exon_variant 2/64
RPA1ENST00000571058.5 linkuse as main transcript downstream_gene_variant 4 ENSP00000461733

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

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 submitterclinical testingAmbry GeneticsJan 26, 2023The c.438T>G (p.N146K) alteration is located in exon 6 (coding exon 6) of the RPA1 gene. This alteration results from a T to G substitution at nucleotide position 438, causing the asparagine (N) at amino acid position 146 to be replaced by a lysine (K). 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
0.19
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
11
DANN
Benign
0.95
DEOGEN2
Benign
0.022
T;T
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.13
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.4
.;M
MutationTaster
Benign
0.97
D
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.3
.;N
REVEL
Benign
0.037
Sift
Benign
0.13
.;T
Sift4G
Benign
0.44
T;T
Polyphen
0.39
.;B
Vest4
0.30
MutPred
0.31
.;Gain of ubiquitination at N146 (P = 0.0104);
MVP
0.58
MPC
0.28
ClinPred
0.17
T
GERP RS
1.1
Varity_R
0.033
gMVP
0.39

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: chr17-1775804; API