17-1842798-C-A

Variant names:

• chr17-1842798-C-A
• rs17338572
• NM_002945.5:c.34-5C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002945.5(RPA1):​c.34-5C>A variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.0008651
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1668 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5	c.34-5C>A		splice_region_variant, intron_variant	Intron 1 of 16	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.-6-5C>A		splice_region_variant, intron_variant	Intron 1 of 16		NP_001342049.1
RPA1	NM_001355121.2	c.34-5C>A		splice_region_variant, intron_variant	Intron 1 of 15		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.34-5C>A		splice_region_variant, intron_variant	Intron 1 of 16	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000570451.5	c.-6-5C>A		splice_region_variant, intron_variant	Intron 1 of 6	3		ENSP00000459788.1
RPA1	ENST00000571058.5	c.-6-5C>A		splice_region_variant, intron_variant	Intron 1 of 5	4		ENSP00000461733.1

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

GnomAD2 exomes AF: 0.00290 AC: 730 AN: 251428 AF XY: 0.00213

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 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 AC: 1338 AN: 33462

Gnomad4 AMR exome AF: 0.00212 AC: 95 AN: 44716

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39686

Gnomad4 SAS exome AF: 0.000151 AC: 13 AN: 86248

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.0000324 AC: 36 AN: 1111856

Gnomad4 Remaining exome AF: 0.00219 AC: 132 AN: 60386

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 AC: 0.0373544 AN: 0.0373544

Gnomad4 AMR AF: 0.00570 AC: 0.00569595 AN: 0.00569595

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000208 AC: 0.000207641 AN: 0.000207641

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000118 AC: 0.000117612 AN: 0.000117612

Gnomad4 OTH AF: 0.00945 AC: 0.0094518 AN: 0.0094518

Alfa AF: 0.00437 Hom.: 5

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
Mutation Taster		=100/0	polymorphism

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;