17-1842798-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002945.5(RPA1):c.34-5C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,613,908 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (36 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (30 hom.)
• Consequence: RPA1 NM_002945.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0008651
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.59

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-1842798-C-A is Benign according to our data. Variant chr17-1842798-C-A is described in ClinVar as [Benign]. Clinvar id is 718295.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.011 (1668/152234) while in subpopulation AFR AF= 0.0374 (1552/41548). AF 95% confidence interval is 0.0358. There are 36 homozygotes in gnomad4. There are 805 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 1665 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA1	NM_002945.5	c.34-5C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000254719.10
RPA1	NM_001355120.2	c.-6-5C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
RPA1	NM_001355121.2	c.34-5C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA1	ENST00000254719.10	c.34-5C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_002945.5	P1
RPA1	ENST00000570451.5	c.-6-5C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		3
RPA1	ENST00000571058.5	c.-6-5C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1665 AN: 152116 Hom.: 36 Cov.: 31

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00570

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00290 AC: 730 AN: 251428 Hom.: 14 AF XY: 0.00213 AC XY: 290 AN XY: 135898

Gnomad AFR exome AF: 0.0399

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00112 AC: 1643 AN: 1461674 Hom.: 30 Cov.: 30 AF XY: 0.000993 AC XY: 722 AN XY: 727140

Gnomad4 AFR exome AF: 0.0400

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.0110 AC: 1668 AN: 152234 Hom.: 36 Cov.: 31 AF XY: 0.0108 AC XY: 805 AN XY: 74436

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.00570

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00404 Hom.: 4

Bravo AF: 0.0130

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.0
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00087
dbscSNV1_RF	Benign	0.038
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: rs17338572; hg19: chr17-1746092;