rs4281767

Variant names:

• chr17-1855928-T-C
• rs4281767
• NM_002945.5:c.361+2739T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-1855928-T-C
• chr17-1855928-T-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002945.5(RPA1):​c.361+2739T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 152,020 control chromosomes in the GnomAD database, including 3,182 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 0.19 (3182 hom., cov: 31)
• Consequence: RPA1 NM_002945.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.651
• Publications: 2 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5	c.361+2739T>C		intron_variant	Intron 5 of 16	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.322+2739T>C		intron_variant	Intron 5 of 16		NP_001342049.1
RPA1	NM_001355121.2	c.361+2739T>C		intron_variant	Intron 5 of 15		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.361+2739T>C		intron_variant	Intron 5 of 16	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000570451.5	c.322+2739T>C		intron_variant	Intron 5 of 6	3		ENSP00000459788.1
RPA1	ENST00000571058.5	c.322+2739T>C		intron_variant	Intron 5 of 5	4		ENSP00000461733.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29546 AN: 151904 Hom.: 3181 Cov.: 31

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.409

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.199

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

GnomAD4 genome AF: 0.194 AC: 29563 AN: 152020 Hom.: 3182 Cov.: 31 AF XY: 0.202 AC XY: 15039 AN XY: 74292

African (AFR) AF: 0.186 AC: 7728 AN: 41484

American (AMR) AF: 0.244 AC: 3729 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 761 AN: 3468

East Asian (EAS) AF: 0.409 AC: 2113 AN: 5162

South Asian (SAS) AF: 0.306 AC: 1470 AN: 4808

European-Finnish (FIN) AF: 0.258 AC: 2718 AN: 10536

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10456 AN: 67986

Other (OTH) AF: 0.196 AC: 414 AN: 2108

Alfa AF: 0.178 Hom.: 337

Bravo AF: 0.194

Asia WGS AF: 0.334 AC: 1156 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.5
DANN	Benign	0.97
PhyloP100		0.65
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: rs4281767; hg19: chr17-1759222;