1-27914065-A-G

Variant names:

• chr1-27914065-A-G
• NM_002946.5:c.115T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002946.5(RPA2):​c.115T>C​(p.Ser39Pro) variant causes a missense, splice region 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. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPA2 NM_002946.5 missense, splice_region
• Scores: Splicing: ADA: 0.001371
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67
• Publications: 0 publications found

Genes affected

RPA2 (HGNC:10290): (replication protein A2) This gene encodes a 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 RPA complex protects 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. The heterotrimeric complex has two different modes of ssDNA binding, a low-affinity and high-affinity mode, determined by which oligonucleotide/oligosaccharide-binding (OB) domains of the complex are utilized, and differing in the length of DNA bound. This subunit contains a single OB domain that participates in high-affinity DNA binding and also contains a winged helix domain at its carboxy terminus, which interacts with many genome maintenance protein. Post-translational modifications of the RPA complex also plays a role in co-ordinating different damage response pathways. [provided by RefSeq, Sep 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16382802).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002946.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA2	NM_002946.5	MANE Select	c.115T>C	p.Ser39Pro	missense splice_region	Exon 2 of 9	NP_002937.1	P15927-1
	RPA2	NM_001297558.1		c.139T>C	p.Ser47Pro	missense splice_region	Exon 2 of 9	NP_001284487.1	P15927-2
	RPA2	NM_001355129.2		c.127T>C	p.Ser43Pro	missense splice_region	Exon 2 of 9	NP_001342058.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA2	ENST00000373912.8	TSL:1 MANE Select	c.115T>C	p.Ser39Pro	missense splice_region	Exon 2 of 9	ENSP00000363021.3	P15927-1
	RPA2	ENST00000313433.11	TSL:1	c.379T>C	p.Ser127Pro	missense splice_region	Exon 1 of 8	ENSP00000363015.3	P15927-3
	RPA2	ENST00000935486.1		c.160T>C	p.Ser54Pro	missense splice_region	Exon 2 of 9	ENSP00000605545.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.042
Sift	Benign	0.26	T
Sift4G	Benign	0.33	T
Polyphen		0.026	B
Vest4		0.13
MutPred		0.28		Loss of phosphorylation at S39 (P = 0.0382)
MVP		0.40
MPC		0.65
ClinPred		0.81	D
GERP RS		4.6
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.54
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.056
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

Other links and lift over

hg19: chr1-28240576; COSMIC: COSV108821390;