17-1844681-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: RPA1 NM_002945.5 synonymous
• Clinical Significance: Not reported in ClinVar
• 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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• 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

GnomAD3 exomes AF: 0.0000719 AC: 18 AN: 250264 Hom.: 0 AF XY: 0.0000518 AC XY: 7 AN XY: 135160

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 SAS exome AF: 0.0000660

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

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000699

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000211

Gnomad4 OTH exome AF: 0.000598

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

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000151

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Not reported in ClinVar

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;