chr17-1888880-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002945.5(RPA1):c.1551+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,599,184 control chromosomes in the GnomAD database, including 35,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.17 ( 2741 hom., cov: 32)

Exomes 𝑓: 0.21 ( 32474 hom. )

Consequence

RPA1
NM_002945.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.988

Publications

19 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 17-1888880-G-A is Benign according to our data. Variant chr17-1888880-G-A is described in ClinVar as Benign. ClinVar VariationId is 2688163.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5 link	c.1551+29G>A	intron_variant	Intron 14 of 16	ENST00000254719.10	NP_002936.1	P27694
RPA1	NM_001355120.2 link	c.1512+29G>A	intron_variant	Intron 14 of 16		NP_001342049.1
RPA1	NM_001355121.2 link	c.1375-2953G>A	intron_variant	Intron 13 of 15		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10 link	c.1551+29G>A		intron_variant	Intron 14 of 16	1	NM_002945.5	ENSP00000254719.4		P27694
RPA1	ENST00000574049.1 link	c.643-2953G>A		intron_variant	Intron 5 of 7	5		ENSP00000461466.1		I3L4R8

Frequencies

GnomAD3 genomes

AF:

0.169

AC:

25691

AN:

152084

Hom.:

2746

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0388

Gnomad AMI

AF:

0.205

Gnomad AMR

AF:

0.211

Gnomad ASJ

AF:

0.204

Gnomad EAS

AF:

0.297

Gnomad SAS

AF:

0.187

Gnomad FIN

AF:

0.269

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.190

GnomAD2 exomes

AF:

0.215

AC:

52365

AN:

243968

AF XY:

0.216

show subpopulations

Gnomad AFR exome

AF:

0.0345

Gnomad AMR exome

AF:

0.233

Gnomad ASJ exome

AF:

0.226

Gnomad EAS exome

AF:

0.299

Gnomad FIN exome

AF:

0.267

Gnomad NFE exome

AF:

0.217

Gnomad OTH exome

AF:

0.219

GnomAD4 exome

AF:

0.208

AC:

300895

AN:

1446982

Hom.:

32474

Cov.:

AF XY:

0.209

AC XY:

149956

AN XY:

717836

show subpopulations

African (AFR)

AF:

0.0336

AC:

1118

AN:

33242

American (AMR)

AF:

0.230

AC:

10200

AN:

44270

Ashkenazi Jewish (ASJ)

AF:

0.216

AC:

5514

AN:

25552

East Asian (EAS)

AF:

0.316

AC:

12440

AN:

39386

South Asian (SAS)

AF:

0.191

AC:

16203

AN:

84936

European-Finnish (FIN)

AF:

0.264

AC:

13967

AN:

52990

Middle Eastern (MID)

AF:

0.244

AC:

1390

AN:

5696

European-Non Finnish (NFE)

AF:

0.207

AC:

228271

AN:

1101158

Other (OTH)

AF:

0.197

AC:

11792

AN:

59752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

11815

23631

35446

47262

59077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7932

15864

23796

31728

39660

<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:

0.169

AC:

25690

AN:

152202

Hom.:

2741

Cov.:

AF XY:

0.173

AC XY:

12845

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0387

AC:

1608

AN:

41552

American (AMR)

AF:

0.211

AC:

3219

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

706

AN:

3468

East Asian (EAS)

AF:

0.297

AC:

1535

AN:

5172

South Asian (SAS)

AF:

0.188

AC:

907

AN:

4830

European-Finnish (FIN)

AF:

0.269

AC:

2842

AN:

10578

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.209

AC:

14219

AN:

67992

Other (OTH)

AF:

0.188

AC:

397

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1050

2101

3151

4202

5252

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.203

Hom.:

5884

Bravo

AF:

0.162

Asia WGS

AF:

0.197

AC:

685

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.34

(source)

DANN

Benign

0.68

PhyloP100

-0.99

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over