17-1897306-C-T

Position:

• chr17-1897306-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.*131C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.779 in 675,836 control chromosomes in the GnomAD database, including 207,667 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 0.73 (41882 hom., cov: 31)
  • Exomes 𝑓: 0.79 (165785 hom.)
• Consequence: RPA1 NM_002945.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0950

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPA1	NM_002945.5	c.*131C>T		3_prime_UTR_variant	17/17	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.*131C>T		3_prime_UTR_variant	17/17		NP_001342049.1
RPA1	NM_001355121.2	c.*131C>T		3_prime_UTR_variant	16/16		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.*131C>T		3_prime_UTR_variant	17/17	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000574049.1	c.*131C>T		3_prime_UTR_variant	8/8	5		ENSP00000461466.1
RPA1	ENST00000573994.1	n.614C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111312 AN: 151924 Hom.: 41880 Cov.: 31

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.767

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.827

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.772

GnomAD4 exome AF: 0.793 AC: 415144 AN: 523794 Hom.: 165785 Cov.: 7 AF XY: 0.788 AC XY: 216028 AN XY: 274032

Gnomad4 AFR exome AF: 0.540

Gnomad4 AMR exome AF: 0.760

Gnomad4 ASJ exome AF: 0.815

Gnomad4 EAS exome AF: 0.831

Gnomad4 SAS exome AF: 0.685

Gnomad4 FIN exome AF: 0.824

Gnomad4 NFE exome AF: 0.813

Gnomad4 OTH exome AF: 0.782

GnomAD4 genome AF: 0.732 AC: 111346 AN: 152042 Hom.: 41882 Cov.: 31 AF XY: 0.735 AC XY: 54629 AN XY: 74322

Gnomad4 AFR AF: 0.545

Gnomad4 AMR AF: 0.767

Gnomad4 ASJ AF: 0.811

Gnomad4 EAS AF: 0.827

Gnomad4 SAS AF: 0.673

Gnomad4 FIN AF: 0.826

Gnomad4 NFE AF: 0.813

Gnomad4 OTH AF: 0.762

Alfa AF: 0.795 Hom.: 68238

Bravo AF: 0.723

Asia WGS AF: 0.692 AC: 2407 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.7
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5030740; hg19: chr17-1800600;