NM_002945.5:c.50G>A

Variant names:

• chr17-1842819-G-A
• NM_002945.5:c.50G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002945.5(RPA1):​c.50G>A​(p.Gly17Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPA1 NM_002945.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35

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]

ACMG classification

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=0.18481442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5	c.50G>A	p.Gly17Glu	missense_variant	Exon 2 of 17	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.11G>A	p.Gly4Glu	missense_variant	Exon 2 of 17		NP_001342049.1
RPA1	NM_001355121.2	c.50G>A	p.Gly17Glu	missense_variant	Exon 2 of 16		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.50G>A	p.Gly17Glu	missense_variant	Exon 2 of 17	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000570451.5	c.11G>A	p.Gly4Glu	missense_variant	Exon 2 of 7	3		ENSP00000459788.1
RPA1	ENST00000571058.5	c.11G>A	p.Gly4Glu	missense_variant	Exon 2 of 6	4		ENSP00000461733.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.69
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;.;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.2	.;.;N
REVEL	Benign	0.088
Sift	Benign	1.0	.;.;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.083	.;.;B
Vest4		0.13
MutPred		0.65		.;.;Loss of catalytic residue at M14 (P = 0.031);
MVP		0.66
MPC		0.33
ClinPred		0.089	T
GERP RS		3.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.22
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-1746113;