rs8077346

chr17-1882839-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002945.5(RPA1):c.1242-973C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 152,066 control chromosomes in the GnomAD database, including 12,173 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 0.36 (12173 hom., cov: 32)
• Consequence: RPA1 NM_002945.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.200

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA1	NM_002945.5	c.1242-973C>T		intron_variant		ENST00000254719.10
RPA1	NM_001355120.2	c.1203-973C>T		intron_variant
RPA1	NM_001355121.2	c.1242-973C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA1	ENST00000254719.10	c.1242-973C>T		intron_variant		1	NM_002945.5	P1
RPA1	ENST00000574049.1	c.510-973C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54941 AN: 151948 Hom.: 12177 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.356

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

GnomAD4 genome AF: 0.361 AC: 54936 AN: 152066 Hom.: 12173 Cov.: 32 AF XY: 0.354 AC XY: 26342 AN XY: 74346

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.283

Gnomad4 ASJ AF: 0.392

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.415

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.352

Alfa AF: 0.469 Hom.: 23222

Bravo AF: 0.339

Asia WGS AF: 0.208 AC: 726 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.2
Dann	Benign	0.57

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

Publications

LitVar

Other links and lift over

dbSNP: rs8077346; hg19: chr17-1786133; COSMIC: COSV54608334; COSMIC: COSV54608334;