17-1844681-C-T

Variant names:

• chr17-1844681-C-T
• rs369379499
• NM_002945.5:c.267C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002945.5(RPA1):​c.267C>T​(p.Asp89Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,609,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: RPA1 NM_002945.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.683

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 17-1844681-C-T is Benign according to our data. Variant chr17-1844681-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3778209.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.683 with no splicing effect.
• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5	c.267C>T	p.Asp89Asp	synonymous_variant	Exon 4 of 17	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.228C>T	p.Asp76Asp	synonymous_variant	Exon 4 of 17		NP_001342049.1
RPA1	NM_001355121.2	c.267C>T	p.Asp89Asp	synonymous_variant	Exon 4 of 16		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.267C>T	p.Asp89Asp	synonymous_variant	Exon 4 of 17	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000570451.5	c.228C>T	p.Asp76Asp	synonymous_variant	Exon 4 of 7	3		ENSP00000459788.1
RPA1	ENST00000571058.5	c.228C>T	p.Asp76Asp	synonymous_variant	Exon 4 of 6	4		ENSP00000461733.1
RPA1	ENST00000571725.1	n.183C>T		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152058 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000719 AC: 18 AN: 250264 AF XY: 0.0000518

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000195 AC: 285 AN: 1457808 Hom.: 0 Cov.: 29 AF XY: 0.000164 AC XY: 119 AN XY: 725202

Gnomad4 AFR exome AF: 0.000180 AC: 6 AN: 33424

Gnomad4 AMR exome AF: 0.0000224 AC: 1 AN: 44640

Gnomad4 ASJ exome AF: 0.0000384 AC: 1 AN: 26018

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39664

Gnomad4 SAS exome AF: 0.0000699 AC: 6 AN: 85876

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53340

Gnomad4 NFE exome AF: 0.000211 AC: 234 AN: 1108836

Gnomad4 Remaining exome AF: 0.000598 AC: 36 AN: 60250

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152058 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74264

Gnomad4 AFR AF: 0.000266 AC: 0.000265713 AN: 0.000265713

Gnomad4 AMR AF: 0.000131 AC: 0.000131199 AN: 0.000131199

Gnomad4 ASJ AF: 0.000288 AC: 0.000288351 AN: 0.000288351

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000221 AC: 0.00022053 AN: 0.00022053

Gnomad4 OTH AF: 0.000479 AC: 0.000478927 AN: 0.000478927

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000151

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RPA1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.2
DANN	Benign	0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs369379499; hg19: chr17-1747975; COSMIC: COSV54611563;