chr17-1897843-G-T

Variant names:

• chr17-1897843-G-T
• rs1051315
• NM_002945.5:c.*668G>T

Variant summary

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

The NM_002945.5(RPA1):​c.*668G>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.059 in 152,752 control chromosomes in the GnomAD database, including 274 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 0.059 (274 hom., cov: 33)
  • Exomes 𝑓: 0.045 (0 hom.)
• Consequence: RPA1 NM_002945.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.49
• Publications: 10 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=-0.29).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0773 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.*668G>T		3_prime_UTR	Exon 17 of 17	NP_002936.1
	RPA1	NM_001355120.2		c.*668G>T		3_prime_UTR	Exon 17 of 17	NP_001342049.1
	RPA1	NM_001355121.2		c.*668G>T		3_prime_UTR	Exon 16 of 16	NP_001342050.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	ENST00000254719.10	TSL:1 MANE Select	c.*668G>T		3_prime_UTR	Exon 17 of 17	ENSP00000254719.4
	RPA1	ENST00000574049.1	TSL:5	c.*668G>T		3_prime_UTR	Exon 8 of 8	ENSP00000461466.1

Frequencies

GnomAD3 genomes AF: 0.0590 AC: 8983 AN: 152146 Hom.: 274 Cov.: 33

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0525

Gnomad ASJ AF: 0.0695

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.0476

Gnomad FIN AF: 0.0516

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.0583

GnomAD4 exome AF: 0.0451 AC: 22 AN: 488 Hom.: 0 Cov.: 0 AF XY: 0.0451 AC XY: 13 AN XY: 288

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.0481 AC: 20 AN: 416

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0172 AC: 1 AN: 58

Other (OTH) AF: 0.125 AC: 1 AN: 8

GnomAD4 genome AF: 0.0590 AC: 8987 AN: 152264 Hom.: 274 Cov.: 33 AF XY: 0.0573 AC XY: 4269 AN XY: 74456

African (AFR) AF: 0.0795 AC: 3303 AN: 41524

American (AMR) AF: 0.0524 AC: 802 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0695 AC: 241 AN: 3470

East Asian (EAS) AF: 0.0256 AC: 133 AN: 5186

South Asian (SAS) AF: 0.0481 AC: 232 AN: 4828

European-Finnish (FIN) AF: 0.0516 AC: 548 AN: 10612

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0525 AC: 3571 AN: 68024

Other (OTH) AF: 0.0572 AC: 121 AN: 2114

Alfa AF: 0.0588 Hom.: 460

Bravo AF: 0.0596

Asia WGS AF: 0.0360 AC: 125 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.94
PhyloP100		6.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1051315; hg19: chr17-1801137;