1-27907814-A-G

Position:

• chr1-27907814-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002946.5(RPA2):​c.118-532T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 152,018 control chromosomes in the GnomAD database, including 8,015 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 0.30 (8015 hom., cov: 32)
• Consequence: RPA2 NM_002946.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.69

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPA2	NM_002946.5	c.118-532T>C		intron_variant		ENST00000373912.8	NP_002937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPA2	ENST00000373912.8	c.118-532T>C		intron_variant		1	NM_002946.5	ENSP00000363021.3
RPA2	ENST00000313433.11	c.382-532T>C		intron_variant		1		ENSP00000363015.3
RPA2	ENST00000373909.7	c.142-532T>C		intron_variant		3		ENSP00000363017.3
RPA2	ENST00000444045.1	c.130-532T>C		intron_variant		5		ENSP00000387649.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45440 AN: 151902 Hom.: 8011 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.376

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.331

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

GnomAD4 genome AF: 0.299 AC: 45454 AN: 152018 Hom.: 8015 Cov.: 32 AF XY: 0.299 AC XY: 22243 AN XY: 74312

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.366

Gnomad4 EAS AF: 0.520

Gnomad4 SAS AF: 0.323

Gnomad4 FIN AF: 0.376

Gnomad4 NFE AF: 0.372

Gnomad4 OTH AF: 0.327

Alfa AF: 0.353 Hom.: 5849

Bravo AF: 0.294

Asia WGS AF: 0.333 AC: 1154 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.6
DANN	Benign	0.63

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

LitVar

Other links and lift over

dbSNP: rs7536088; hg19: chr1-28234325;