1-27891589-T-C

Variant names:

• chr1-27891589-T-C
• rs7356
• NM_002946.5:c.*574A>G

Variant summary

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

The ENST00000373912.8(RPA2):​c.*574A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 152,308 control chromosomes in the GnomAD database, including 15,207 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 (15197 hom., cov: 32)
  • Exomes 𝑓: 0.30 (10 hom.)
• Consequence: RPA2 ENST00000373912.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.78
• Publications: 31 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000373912.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA2	NM_002946.5	MANE Select	c.*574A>G		3_prime_UTR	Exon 9 of 9	NP_002937.1
	RPA2	NM_001297558.1		c.*574A>G		3_prime_UTR	Exon 9 of 9	NP_001284487.1
	RPA2	NM_001355129.2		c.*574A>G		3_prime_UTR	Exon 9 of 9	NP_001342058.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA2	ENST00000373912.8	TSL:1 MANE Select	c.*574A>G		3_prime_UTR	Exon 9 of 9	ENSP00000363021.3
	RPA2	ENST00000419958.5	TSL:3	c.*134A>G		3_prime_UTR	Exon 5 of 5	ENSP00000413541.1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66474 AN: 151954 Hom.: 15168 Cov.: 32

Gnomad AFR AF: 0.578

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.327

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.436

GnomAD4 exome AF: 0.299 AC: 70 AN: 234 Hom.: 10 Cov.: 0 AF XY: 0.300 AC XY: 42 AN XY: 140

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AF: 0.324 AC: 11 AN: 34

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.174 AC: 8 AN: 46

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.321 AC: 45 AN: 140

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.438 AC: 66547 AN: 152074 Hom.: 15197 Cov.: 32 AF XY: 0.433 AC XY: 32178 AN XY: 74342

African (AFR) AF: 0.579 AC: 24011 AN: 41472

American (AMR) AF: 0.385 AC: 5887 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1408 AN: 3468

East Asian (EAS) AF: 0.520 AC: 2692 AN: 5180

South Asian (SAS) AF: 0.325 AC: 1571 AN: 4828

European-Finnish (FIN) AF: 0.375 AC: 3958 AN: 10548

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

European-Non Finnish (NFE) AF: 0.375 AC: 25470 AN: 67990

Other (OTH) AF: 0.431 AC: 911 AN: 2112

Alfa AF: 0.398 Hom.: 37231

Bravo AF: 0.452

Asia WGS AF: 0.362 AC: 1257 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.11
DANN	Benign	0.45
PhyloP100		-2.8
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)		0.0		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: rs7356; hg19: chr1-28218100;