rs8077346

Variant names:

• chr17-1882839-C-T
• rs8077346
• NM_002945.5:c.1242-973C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002945.5(RPA1):​c.1242-973C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 152,066 control chromosomes in the GnomAD database, including 12,173 homozygotes. 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 0.36 (12173 hom., cov: 32)
• Consequence: RPA1 NM_002945.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.200
• Publications: 5 publications found

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]

RPA1 Gene-Disease associations (from GenCC):

• pulmonary fibrosis and/or bone marrow failure, telomere-related, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002945.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	NM_002945.5	MANE Select	c.1242-973C>T		intron	N/A	NP_002936.1
	RPA1	NM_001355120.2		c.1203-973C>T		intron	N/A	NP_001342049.1
	RPA1	NM_001355121.2		c.1242-973C>T		intron	N/A	NP_001342050.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	ENST00000254719.10	TSL:1 MANE Select	c.1242-973C>T		intron	N/A	ENSP00000254719.4
	RPA1	ENST00000574049.1	TSL:5	c.510-973C>T		intron	N/A	ENSP00000461466.1

Frequencies

GnomAD3 genomes AF: 0.362 AC: 54941 AN: 151948 Hom.: 12177 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.694

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.356

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.361 AC: 54936 AN: 152066 Hom.: 12173 Cov.: 32 AF XY: 0.354 AC XY: 26342 AN XY: 74346

African (AFR) AF: 0.137 AC: 5683 AN: 41500

American (AMR) AF: 0.283 AC: 4320 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 1361 AN: 3470

East Asian (EAS) AF: 0.234 AC: 1210 AN: 5178

South Asian (SAS) AF: 0.264 AC: 1276 AN: 4826

European-Finnish (FIN) AF: 0.415 AC: 4376 AN: 10548

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.518 AC: 35225 AN: 67950

Other (OTH) AF: 0.352 AC: 742 AN: 2110

Alfa AF: 0.457 Hom.: 28274

Bravo AF: 0.339

Asia WGS AF: 0.208 AC: 726 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.2
DANN	Benign	0.57
PhyloP100		0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8077346; hg19: chr17-1786133; COSMIC: COSV54608334; COSMIC: COSV54608334;