17-1896793-A-G

Variant names:

• chr17-1896793-A-G
• rs4790838
• NM_002945.5:c.1747-278A>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.1747-278A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 152,150 control chromosomes in the GnomAD database, including 5,954 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 0.27 (5954 hom., cov: 32)
• Consequence: RPA1 NM_002945.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.157
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	NM_002945.5	MANE Select	c.1747-278A>G		intron	N/A	NP_002936.1
	RPA1	NM_001355120.2		c.1708-278A>G		intron	N/A	NP_001342049.1
	RPA1	NM_001355121.2		c.1570-278A>G		intron	N/A	NP_001342050.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	ENST00000254719.10	TSL:1 MANE Select	c.1747-278A>G		intron	N/A	ENSP00000254719.4
	RPA1	ENST00000574049.1	TSL:5	c.838-278A>G		intron	N/A	ENSP00000461466.1
	RPA1	ENST00000573994.1	TSL:2	n.379-278A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40943 AN: 152032 Hom.: 5953 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.289

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

GnomAD4 genome AF: 0.269 AC: 40958 AN: 152150 Hom.: 5954 Cov.: 32 AF XY: 0.271 AC XY: 20152 AN XY: 74388

African (AFR) AF: 0.165 AC: 6831 AN: 41522

American (AMR) AF: 0.276 AC: 4225 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1186 AN: 3472

East Asian (EAS) AF: 0.351 AC: 1817 AN: 5170

South Asian (SAS) AF: 0.249 AC: 1203 AN: 4828

European-Finnish (FIN) AF: 0.378 AC: 3995 AN: 10578

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.304 AC: 20694 AN: 67976

Other (OTH) AF: 0.285 AC: 603 AN: 2114

Alfa AF: 0.293 Hom.: 17272

Bravo AF: 0.262

Asia WGS AF: 0.254 AC: 882 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.6
DANN	Benign	0.73
PhyloP100		0.16
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: rs4790838; hg19: chr17-1800087; COSMIC: COSV54613078;