dbSNP rs1051315: RPA1:c.*668G>T (chr17-1897843-G-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_002945.5(RPA1):c.*668G>T variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.059 in 152,752 control chromosomes in the GnomAD database, including 274 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 0.059 ( 274 hom., cov: 33)

Exomes 𝑓: 0.045 ( 0 hom. )

Consequence

RPA1
NM_002945.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.49

Publications

10 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5 link	c.*668G>T	3_prime_UTR_variant	Exon 17 of 17	ENST00000254719.10	NP_002936.1	P27694
RPA1	NM_001355120.2 link	c.*668G>T	3_prime_UTR_variant	Exon 17 of 17		NP_001342049.1
RPA1	NM_001355121.2 link	c.*668G>T	3_prime_UTR_variant	Exon 16 of 16		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10 link	c.*668G>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_002945.5	ENSP00000254719.4		P27694
RPA1	ENST00000574049.1 link	c.*668G>T		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000461466.1		I3L4R8

Frequencies

GnomAD3 genomes

AF:

0.0590

AC:

8983

AN:

152146

Hom.:

274

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0796

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0525

Gnomad ASJ

AF:

0.0695

Gnomad EAS

AF:

0.0256

Gnomad SAS

AF:

0.0476

Gnomad FIN

AF:

0.0516

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0525

Gnomad OTH

AF:

0.0583

GnomAD4 exome

AF:

0.0451

AC:

AN:

488

Hom.:

Cov.:

AF XY:

0.0451

AC XY:

AN XY:

288

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.0481

AC:

AN:

416

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0172

AC:

AN:

Other (OTH)

AF:

0.125

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0590

AC:

8987

AN:

152264

Hom.:

274

Cov.:

AF XY:

0.0573

AC XY:

4269

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0795

AC:

3303

AN:

41524

American (AMR)

AF:

0.0524

AC:

802

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0695

AC:

241

AN:

3470

East Asian (EAS)

AF:

0.0256

AC:

133

AN:

5186

South Asian (SAS)

AF:

0.0481

AC:

232

AN:

4828

European-Finnish (FIN)

AF:

0.0516

AC:

548

AN:

10612

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0525

AC:

3571

AN:

68024

Other (OTH)

AF:

0.0572

AC:

121

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

447

894

1341

1788

2235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<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:

0.0588

Hom.:

460

Bravo

AF:

0.0596

Asia WGS

AF:

0.0360

AC:

125

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

6.5

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)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over