rs3766396

Variant names:

• chr1-27895043-A-G
• rs3766396
• NM_002946.5:c.526-646T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002946.5(RPA2):​c.526-646T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 151,896 control chromosomes in the GnomAD database, including 15,186 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.44 (15186 hom., cov: 31)
• Consequence: RPA2 NM_002946.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.366
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA2	NM_002946.5	c.526-646T>C		intron_variant	Intron 6 of 8	ENST00000373912.8	NP_002937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA2	ENST00000373912.8	c.526-646T>C		intron_variant	Intron 6 of 8	1	NM_002946.5	ENSP00000363021.3
RPA2	ENST00000313433.11	c.790-646T>C		intron_variant	Intron 5 of 7	1		ENSP00000363015.3
RPA2	ENST00000373909.7	c.550-646T>C		intron_variant	Intron 6 of 8	3		ENSP00000363017.3
RPA2	ENST00000419958.5	c.82-646T>C		intron_variant	Intron 1 of 4	3		ENSP00000413541.1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66425 AN: 151778 Hom.: 15156 Cov.: 31

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.436

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.438 AC: 66499 AN: 151896 Hom.: 15186 Cov.: 31 AF XY: 0.433 AC XY: 32153 AN XY: 74230

African (AFR) AF: 0.579 AC: 23990 AN: 41434

American (AMR) AF: 0.386 AC: 5890 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1409 AN: 3466

East Asian (EAS) AF: 0.521 AC: 2689 AN: 5166

South Asian (SAS) AF: 0.325 AC: 1563 AN: 4806

European-Finnish (FIN) AF: 0.376 AC: 3958 AN: 10540

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25454 AN: 67922

Other (OTH) AF: 0.431 AC: 905 AN: 2100

Alfa AF: 0.419 Hom.: 2929

Bravo AF: 0.452

Asia WGS AF: 0.362 AC: 1257 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.5
DANN	Benign	0.77
PhyloP100		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3766396; hg19: chr1-28221554;