chr17-1873606-G-T

Variant names:

• chr17-1873606-G-T
• rs7503173
• NM_002945.5:c.454+1080G>T

Variant summary

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

The NM_002945.5(RPA1):​c.454+1080G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 151,812 control chromosomes in the GnomAD database, including 8,130 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 0.29 (8130 hom., cov: 30)
• Consequence: RPA1 NM_002945.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.536
• Publications: 5 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 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.454+1080G>T		intron	N/A	NP_002936.1
	RPA1	NM_001355120.2		c.415+1080G>T		intron	N/A	NP_001342049.1
	RPA1	NM_001355121.2		c.454+1080G>T		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.454+1080G>T		intron	N/A	ENSP00000254719.4
	RPA1	ENST00000852058.1		c.595+1080G>T		intron	N/A	ENSP00000522117.1
	RPA1	ENST00000852055.1		c.547+1080G>T		intron	N/A	ENSP00000522114.1

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43815 AN: 151694 Hom.: 8100 Cov.: 30

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.279

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

GnomAD4 genome AF: 0.289 AC: 43896 AN: 151812 Hom.: 8130 Cov.: 30 AF XY: 0.294 AC XY: 21841 AN XY: 74180

African (AFR) AF: 0.509 AC: 21073 AN: 41378

American (AMR) AF: 0.288 AC: 4392 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 761 AN: 3470

East Asian (EAS) AF: 0.409 AC: 2109 AN: 5154

South Asian (SAS) AF: 0.308 AC: 1482 AN: 4806

European-Finnish (FIN) AF: 0.260 AC: 2729 AN: 10504

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10591 AN: 67938

Other (OTH) AF: 0.275 AC: 579 AN: 2102

Alfa AF: 0.147 Hom.: 489

Bravo AF: 0.302

Asia WGS AF: 0.352 AC: 1221 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.68
DANN	Benign	0.34
PhyloP100		-0.54
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: rs7503173; hg19: chr17-1776900;