Genetic Variant RPA1:c.*720C>T (chr17-1897895-C-T) – 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.*720C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 152,500 control chromosomes in the GnomAD database, including 21,434 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 0.52 ( 21373 hom., cov: 33)

Exomes 𝑓: 0.57 ( 61 hom. )

Consequence

RPA1
NM_002945.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.63

Publications

35 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=-0.59).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
RPA1	NM_002945.5 link	c.*720C>T	3_prime_UTR_variant	Exon 17 of 17	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2 link	c.*720C>T	3_prime_UTR_variant	Exon 17 of 17		NP_001342049.1
RPA1	NM_001355121.2 link	c.*720C>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.*720C>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000574049.1 link	c.*720C>T		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000461466.1

Frequencies

GnomAD3 genomes

AF:

0.520

AC:

79076

AN:

151984

Hom.:

21376

Cov.:

show subpopulations

Gnomad AFR

AF:

0.381

Gnomad AMI

AF:

0.632

Gnomad AMR

AF:

0.542

Gnomad ASJ

AF:

0.574

Gnomad EAS

AF:

0.551

Gnomad SAS

AF:

0.390

Gnomad FIN

AF:

0.564

Gnomad MID

AF:

0.554

Gnomad NFE

AF:

0.595

Gnomad OTH

AF:

0.542

GnomAD4 exome

AF:

0.570

AC:

227

AN:

398

Hom.:

Cov.:

AF XY:

0.573

AC XY:

134

AN XY:

234

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.563

AC:

216

AN:

384

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.875

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.520

AC:

79085

AN:

152102

Hom.:

21373

Cov.:

AF XY:

0.518

AC XY:

38500

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.380

AC:

15767

AN:

41472

American (AMR)

AF:

0.542

AC:

8284

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.574

AC:

1989

AN:

3468

East Asian (EAS)

AF:

0.550

AC:

2843

AN:

5166

South Asian (SAS)

AF:

0.390

AC:

1882

AN:

4830

European-Finnish (FIN)

AF:

0.564

AC:

5968

AN:

10580

Middle Eastern (MID)

AF:

0.558

AC:

164

AN:

294

European-Non Finnish (NFE)

AF:

0.595

AC:

40482

AN:

67984

Other (OTH)

AF:

0.534

AC:

1130

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1886

3772

5659

7545

9431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

688

1376

2064

2752

3440

<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:

0.567

Hom.:

76413

Bravo

AF:

0.517

Asia WGS

AF:

0.403

AC:

1403

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

2.6

Mutation Taster

=99/1

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