1-27914145-G-T

Variant names:

• chr1-27914145-G-T
• rs776471331
• NM_002946.5:c.35C>A

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.35C>A​(p.Ser12Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S12F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RPA2 NM_002946.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.23
• Publications: 1 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=0.17702225).

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.35C>A	p.Ser12Tyr	missense	Exon 2 of 9	NP_002937.1	P15927-1
	RPA2	NM_001297558.1		c.59C>A	p.Ser20Tyr	missense	Exon 2 of 9	NP_001284487.1	P15927-2
	RPA2	NM_001355129.2		c.47C>A	p.Ser16Tyr	missense	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.35C>A	p.Ser12Tyr	missense	Exon 2 of 9	ENSP00000363021.3	P15927-1
	RPA2	ENST00000313433.11	TSL:1	c.299C>A	p.Ser100Tyr	missense	Exon 1 of 8	ENSP00000363015.3	P15927-3
	RPA2	ENST00000935486.1		c.80C>A	p.Ser27Tyr	missense	Exon 2 of 9	ENSP00000605545.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250516 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.098
Sift	Benign	0.033	D
Sift4G	Uncertain	0.010	D
Polyphen		0.65	P
Vest4		0.55
MutPred		0.27		Loss of glycosylation at S12 (P = 0.0059)
MVP		0.45
MPC		0.44
ClinPred		0.19	T
GERP RS		3.6
PromoterAI		-0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.096
gMVP		0.55
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs776471331; hg19: chr1-28240656;