dbSNP rs3744767: RPA1:c.*463T>C (chr17-1897638-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002945.5(RPA1):c.*463T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 161,142 control chromosomes in the GnomAD database, including 4,106 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 0.22 ( 3862 hom., cov: 32)

Exomes 𝑓: 0.21 ( 244 hom. )

Consequence

RPA1
NM_002945.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.781

Publications

22 publications found

Variant links:

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)

RPA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5 link	c.*463T>C	3_prime_UTR_variant	Exon 17 of 17	ENST00000254719.10	NP_002936.1	P27694
RPA1	NM_001355120.2 link	c.*463T>C	3_prime_UTR_variant	Exon 17 of 17		NP_001342049.1
RPA1	NM_001355121.2 link	c.*463T>C	3_prime_UTR_variant	Exon 16 of 16		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RPA1	ENST00000254719.10 link	c.*463T>C	3_prime_UTR_variant	Exon 17 of 17	1	NM_002945.5	ENSP00000254719.4	P27694
RPA1	ENST00000574049.1 link	c.*463T>C	3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000461466.1	I3L4R8
RPA1	ENST00000573994.1 link	n.*102T>C	downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

33871

AN:

151934

Hom.:

3869

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.311

Gnomad AMR

AF:

0.232

Gnomad ASJ

AF:

0.247

Gnomad EAS

AF:

0.304

Gnomad SAS

AF:

0.261

Gnomad FIN

AF:

0.273

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.231

Gnomad OTH

AF:

0.245

GnomAD4 exome

AF:

0.210

AC:

1906

AN:

9090

Hom.:

244

Cov.:

AF XY:

0.211

AC XY:

1005

AN XY:

4770

show subpopulations

African (AFR)

AF:

0.107

AC:

AN:

American (AMR)

AF:

0.222

AC:

537

AN:

2420

Ashkenazi Jewish (ASJ)

AF:

0.188

AC:

AN:

East Asian (EAS)

AF:

0.232

AC:

AN:

142

South Asian (SAS)

AF:

0.224

AC:

308

AN:

1374

European-Finnish (FIN)

AF:

0.287

AC:

AN:

178

Middle Eastern (MID)

AF:

0.188

AC:

AN:

European-Non Finnish (NFE)

AF:

0.200

AC:

898

AN:

4498

Other (OTH)

AF:

0.166

AC:

AN:

386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

145

217

290

362

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.223

AC:

33893

AN:

152052

Hom.:

3862

Cov.:

AF XY:

0.228

AC XY:

16910

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.175

AC:

7249

AN:

41494

American (AMR)

AF:

0.233

AC:

3557

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.247

AC:

858

AN:

3472

East Asian (EAS)

AF:

0.304

AC:

1566

AN:

5148

South Asian (SAS)

AF:

0.261

AC:

1255

AN:

4816

European-Finnish (FIN)

AF:

0.273

AC:

2872

AN:

10536

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.231

AC:

15678

AN:

67986

Other (OTH)

AF:

0.243

AC:

512

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1363

2726

4088

5451

6814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.226

Hom.:

5817

Bravo

AF:

0.217

Asia WGS

AF:

0.284

AC:

984

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

4.4

(source)

DANN

Benign

0.79

PhyloP100

-0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over