NM_002945.5:c.268G>T

Variant names:

• chr17-1844682-G-T
• NM_002945.5:c.268G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002945.5(RPA1):​c.268G>T​(p.Gly90*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000686 in 1,457,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RPA1 NM_002945.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.58

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5	c.268G>T	p.Gly90*	stop_gained	Exon 4 of 17	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.229G>T	p.Gly77*	stop_gained	Exon 4 of 17		NP_001342049.1
RPA1	NM_001355121.2	c.268G>T	p.Gly90*	stop_gained	Exon 4 of 16		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.268G>T	p.Gly90*	stop_gained	Exon 4 of 17	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000570451.5	c.229G>T	p.Gly77*	stop_gained	Exon 4 of 7	3		ENSP00000459788.1
RPA1	ENST00000571058.5	c.229G>T	p.Gly77*	stop_gained	Exon 4 of 6	4		ENSP00000461733.1
RPA1	ENST00000571725.1	n.184G>T		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457554 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.93
GERP RS		6.0
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-1747976;