rs12727

Variant names:

• chr17-1897771-G-C
• rs12727
• NM_002945.5:c.*596G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002945.5(RPA1):​c.*596G>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.218 in 153,584 control chromosomes in the GnomAD database, including 3,886 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 0.22 (3869 hom., cov: 32)
  • Exomes 𝑓: 0.17 (17 hom.)
• Consequence: RPA1 NM_002945.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.49
• Publications: 16 publications found

Genes affected

RPA1 (HGNC:10289): (replication protein A1) This gene encodes the largest 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 nucleoprotein complex protects the 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. This subunit contains four oligonucleotide/oligosaccharide-binding (OB) domains, though the majority of ssDNA binding occurs in two of these domains. The heterotrimeric complex has two different modes of ssDNA binding, a low-affinity and high-affinity mode, determined by which ssDNA binding domains are utilized. The different binding modes differ in the length of DNA bound and in the proteins with which it interacts, thereby playing a role in regulating different genomic maintenance pathways. [provided by RefSeq, Sep 2017]

RPA1 Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure, telomere-related, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5	c.*596G>C		3_prime_UTR_variant	Exon 17 of 17	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.*596G>C		3_prime_UTR_variant	Exon 17 of 17		NP_001342049.1
RPA1	NM_001355121.2	c.*596G>C		3_prime_UTR_variant	Exon 16 of 16		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.*596G>C		3_prime_UTR_variant	Exon 17 of 17	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000574049.1	c.*596G>C		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000461466.1
RPA1	ENST00000573994.1	n.*235G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33171 AN: 152016 Hom.: 3854 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.168 AC: 243 AN: 1450 Hom.: 17 Cov.: 0 AF XY: 0.190 AC XY: 143 AN XY: 754

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.168 AC: 35 AN: 208

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

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

South Asian (SAS) AF: 0.100 AC: 4 AN: 40

European-Finnish (FIN) AF: 0.177 AC: 75 AN: 424

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.164 AC: 119 AN: 726

Other (OTH) AF: 0.188 AC: 9 AN: 48

GnomAD4 genome AF: 0.218 AC: 33234 AN: 152134 Hom.: 3869 Cov.: 32 AF XY: 0.217 AC XY: 16124 AN XY: 74374

African (AFR) AF: 0.288 AC: 11948 AN: 41470

American (AMR) AF: 0.216 AC: 3294 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 670 AN: 3472

East Asian (EAS) AF: 0.148 AC: 765 AN: 5180

South Asian (SAS) AF: 0.289 AC: 1397 AN: 4830

European-Finnish (FIN) AF: 0.174 AC: 1846 AN: 10592

Middle Eastern (MID) AF: 0.199 AC: 58 AN: 292

European-Non Finnish (NFE) AF: 0.188 AC: 12755 AN: 67994

Other (OTH) AF: 0.207 AC: 439 AN: 2116

Alfa AF: 0.206 Hom.: 474

Bravo AF: 0.222

Asia WGS AF: 0.261 AC: 908 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.93
PhyloP100		6.5
Mutation Taster		=99/1	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: rs12727; hg19: chr17-1801065;