17-1898298-A-G

Variant names:

• chr17-1898298-A-G
• rs9914073
• NM_002945.5:c.*1123A>G

Variant summary

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

The NM_002945.5(RPA1):​c.*1123A>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 0.21 in 152,132 control chromosomes in the GnomAD database, including 3,454 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 0.21 (3454 hom., cov: 33)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: RPA1 NM_002945.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.21
• Publications: 19 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=-0.42).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5	c.*1123A>G		3_prime_UTR_variant	Exon 17 of 17	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.*1123A>G		3_prime_UTR_variant	Exon 17 of 17		NP_001342049.1
RPA1	NM_001355121.2	c.*1123A>G		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.*1123A>G		3_prime_UTR_variant	Exon 17 of 17	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000574049.1	c.*1123A>G		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000461466.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31955 AN: 152010 Hom.: 3458 Cov.: 33

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.225

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.210 AC: 31976 AN: 152128 Hom.: 3454 Cov.: 33 AF XY: 0.215 AC XY: 16015 AN XY: 74380

African (AFR) AF: 0.158 AC: 6552 AN: 41522

American (AMR) AF: 0.224 AC: 3419 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 840 AN: 3460

East Asian (EAS) AF: 0.274 AC: 1419 AN: 5176

South Asian (SAS) AF: 0.286 AC: 1376 AN: 4816

European-Finnish (FIN) AF: 0.260 AC: 2750 AN: 10568

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14809 AN: 67988

Other (OTH) AF: 0.222 AC: 469 AN: 2112

Alfa AF: 0.213 Hom.: 13894

Bravo AF: 0.204

Asia WGS AF: 0.287 AC: 996 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Benign	0.75
PhyloP100		3.2
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: rs9914073; hg19: chr17-1801592;