NM_002945.5:c.455-1528A>G

Variant names:

• chr17-1874133-A-G
• rs7501623
• NM_002945.5:c.455-1528A>G

Variant summary

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

The NM_002945.5(RPA1):​c.455-1528A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 151,256 control chromosomes in the GnomAD database, including 3,234 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 0.20 (3234 hom., cov: 30)
• Consequence: RPA1 NM_002945.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460
• Publications: 9 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: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002945.5. 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
	RPA1	NM_002945.5	MANE Select	c.455-1528A>G		intron	N/A	NP_002936.1	P27694
	RPA1	NM_001355120.2		c.416-1528A>G		intron	N/A	NP_001342049.1
	RPA1	NM_001355121.2		c.455-1528A>G		intron	N/A	NP_001342050.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	ENST00000254719.10	TSL:1 MANE Select	c.455-1528A>G		intron	N/A	ENSP00000254719.4	P27694
	RPA1	ENST00000852058.1		c.596-1528A>G		intron	N/A	ENSP00000522117.1
	RPA1	ENST00000852055.1		c.548-1528A>G		intron	N/A	ENSP00000522114.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29685 AN: 151140 Hom.: 3232 Cov.: 30

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.198

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

GnomAD4 genome AF: 0.196 AC: 29705 AN: 151256 Hom.: 3234 Cov.: 30 AF XY: 0.204 AC XY: 15100 AN XY: 73856

African (AFR) AF: 0.186 AC: 7656 AN: 41112

American (AMR) AF: 0.245 AC: 3721 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 759 AN: 3460

East Asian (EAS) AF: 0.408 AC: 2109 AN: 5164

South Asian (SAS) AF: 0.309 AC: 1479 AN: 4782

European-Finnish (FIN) AF: 0.264 AC: 2736 AN: 10380

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10663 AN: 67894

Other (OTH) AF: 0.195 AC: 409 AN: 2096

Alfa AF: 0.177 Hom.: 1504

Bravo AF: 0.194

Asia WGS AF: 0.331 AC: 1145 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.67
PhyloP100		-0.046
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: rs7501623; hg19: chr17-1777427;