NM_002945.5:c.273-44A>G

Variant names:

• chr17-1853057-A-G
• rs2287321
• NM_002945.5:c.273-44A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002945.5(RPA1):​c.273-44A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 1,474,262 control chromosomes in the GnomAD database, including 121,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.41 (13187 hom., cov: 33)
  • Exomes 𝑓: 0.40 (108264 hom.)
• Consequence: RPA1 NM_002945.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.128
• Publications: 14 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 17-1853057-A-G is Benign according to our data. Variant chr17-1853057-A-G is described in ClinVar as Benign. ClinVar VariationId is 2687984.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5	c.273-44A>G		intron_variant	Intron 4 of 16	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.234-44A>G		intron_variant	Intron 4 of 16		NP_001342049.1
RPA1	NM_001355121.2	c.273-44A>G		intron_variant	Intron 4 of 15		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.273-44A>G		intron_variant	Intron 4 of 16	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000570451.5	c.234-44A>G		intron_variant	Intron 4 of 6	3		ENSP00000459788.1
RPA1	ENST00000571058.5	c.234-44A>G		intron_variant	Intron 4 of 5	4		ENSP00000461733.1
RPA1	ENST00000571725.1	n.189-44A>G		intron_variant	Intron 2 of 3	5

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62559 AN: 151896 Hom.: 13183 Cov.: 33

Gnomad AFR AF: 0.387

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.427

GnomAD2 exomes AF: 0.443 AC: 110242 AN: 248888 AF XY: 0.438

Gnomad AFR exome AF: 0.388

Gnomad AMR exome AF: 0.567

Gnomad ASJ exome AF: 0.441

Gnomad EAS exome AF: 0.533

Gnomad FIN exome AF: 0.507

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.400 AC: 528959 AN: 1322248 Hom.: 108264 Cov.: 19 AF XY: 0.402 AC XY: 267312 AN XY: 665622

African (AFR) AF: 0.392 AC: 12010 AN: 30634

American (AMR) AF: 0.559 AC: 24609 AN: 44004

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 11165 AN: 25244

East Asian (EAS) AF: 0.537 AC: 20895 AN: 38908

South Asian (SAS) AF: 0.446 AC: 37060 AN: 83014

European-Finnish (FIN) AF: 0.496 AC: 26427 AN: 53286

Middle Eastern (MID) AF: 0.468 AC: 2584 AN: 5526

European-Non Finnish (NFE) AF: 0.377 AC: 371473 AN: 986002

Other (OTH) AF: 0.409 AC: 22736 AN: 55630

GnomAD4 genome AF: 0.412 AC: 62591 AN: 152014 Hom.: 13187 Cov.: 33 AF XY: 0.419 AC XY: 31094 AN XY: 74296

African (AFR) AF: 0.387 AC: 16045 AN: 41466

American (AMR) AF: 0.493 AC: 7529 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1448 AN: 3466

East Asian (EAS) AF: 0.534 AC: 2763 AN: 5174

South Asian (SAS) AF: 0.449 AC: 2165 AN: 4818

European-Finnish (FIN) AF: 0.510 AC: 5374 AN: 10540

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25967 AN: 67960

Other (OTH) AF: 0.424 AC: 895 AN: 2110

Alfa AF: 0.394 Hom.: 51004

Bravo AF: 0.414

Asia WGS AF: 0.484 AC: 1678 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 78% of patients studied by a panel of primary immunodeficiencies. Number of patients: 74. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.6
DANN	Benign	0.33
PhyloP100		-0.13
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: rs2287321; hg19: chr17-1756351;