chr17-1897638-T-C

Position:

• chr17-1897638-T-C

Variant summary

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

The ENST00000254719.10(RPA1):​c.*463T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 161,142 control chromosomes in the GnomAD database, including 4,106 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 0.22 (3862 hom., cov: 32)
  • Exomes 𝑓: 0.21 (244 hom.)
• Consequence: RPA1 ENST00000254719.10 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.781

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=-0.62).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPA1	NM_002945.5	c.*463T>C		3_prime_UTR_variant	17/17	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.*463T>C		3_prime_UTR_variant	17/17		NP_001342049.1
RPA1	NM_001355121.2	c.*463T>C		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.*463T>C		3_prime_UTR_variant	17/17	1	NM_002945.5	ENSP00000254719	P1
RPA1	ENST00000574049.1	c.*463T>C		3_prime_UTR_variant	8/8	5		ENSP00000461466

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33871 AN: 151934 Hom.: 3869 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.273

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.245

GnomAD4 exome AF: 0.210 AC: 1906 AN: 9090 Hom.: 244 Cov.: 0 AF XY: 0.211 AC XY: 1005 AN XY: 4770

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.222

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.232

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.287

Gnomad4 NFE exome AF: 0.200

Gnomad4 OTH exome AF: 0.166

GnomAD4 genome AF: 0.223 AC: 33893 AN: 152052 Hom.: 3862 Cov.: 32 AF XY: 0.228 AC XY: 16910 AN XY: 74304

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.273

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.243

Alfa AF: 0.226 Hom.: 4030

Bravo AF: 0.217

Asia WGS AF: 0.284 AC: 984 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.4
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3744767; hg19: chr17-1800932;