Genetic Variant NM_002945.5:c.12A>G (chr17-1830105-A-G) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_002945.5(RPA1):c.12A>G(p.Gln4Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 1,249,336 control chromosomes in the GnomAD database, including 354,203 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.68 ( 36363 hom., cov: 31)

Exomes 𝑓: 0.76 ( 317840 hom. )

Consequence

RPA1
NM_002945.5 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.23

Publications

24 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 links:

SMYD4 (HGNC:21067): (SET and MYND domain containing 4) Predicted to enable metal ion binding activity and methyltransferase activity. Involved in heart development. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SMYD4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 17-1830105-A-G is Benign according to our data. Variant chr17-1830105-A-G is described in ClinVar as Benign. ClinVar VariationId is 2688031.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.23 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002945.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPA1	NM_002945.5	MANE Select	c.12A>G	p.Gln4Gln	synonymous	Exon 1 of 17	NP_002936.1	P27694
RPA1	NM_001355121.2		c.12A>G	p.Gln4Gln	synonymous	Exon 1 of 16	NP_001342050.1
RPA1	NM_001355120.2		c.-36A>G		5_prime_UTR	Exon 1 of 17	NP_001342049.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPA1	ENST00000254719.10	TSL:1 MANE Select	c.12A>G	p.Gln4Gln	synonymous	Exon 1 of 17	ENSP00000254719.4	P27694
RPA1	ENST00000852058.1		c.12A>G	p.Gln4Gln	synonymous	Exon 1 of 18	ENSP00000522117.1
RPA1	ENST00000852055.1		c.12A>G	p.Gln4Gln	synonymous	Exon 1 of 18	ENSP00000522114.1

Frequencies

GnomAD3 genomes

AF:

0.681

AC:

103513

AN:

151928

Hom.:

36340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.644

Gnomad AMI

AF:

0.884

Gnomad AMR

AF:

0.520

Gnomad ASJ

AF:

0.666

Gnomad EAS

AF:

0.378

Gnomad SAS

AF:

0.502

Gnomad FIN

AF:

0.663

Gnomad MID

AF:

0.707

Gnomad NFE

AF:

0.778

Gnomad OTH

AF:

0.665

GnomAD2 exomes

AF:

0.662

AC:

14278

AN:

21576

AF XY:

0.667

show subpopulations

Gnomad AFR exome

AF:

0.620

Gnomad AMR exome

AF:

0.465

Gnomad ASJ exome

AF:

0.643

Gnomad EAS exome

AF:

0.360

Gnomad FIN exome

AF:

0.645

Gnomad NFE exome

AF:

0.757

Gnomad OTH exome

AF:

0.688

GnomAD4 exome

AF:

0.755

AC:

828869

AN:

1097292

Hom.:

317840

Cov.:

AF XY:

0.754

AC XY:

391088

AN XY:

518374

show subpopulations

African (AFR)

AF:

0.638

AC:

14725

AN:

23098

American (AMR)

AF:

0.473

AC:

4056

AN:

8568

Ashkenazi Jewish (ASJ)

AF:

0.663

AC:

9533

AN:

14368

East Asian (EAS)

AF:

0.333

AC:

8890

AN:

26668

South Asian (SAS)

AF:

0.513

AC:

10092

AN:

19686

European-Finnish (FIN)

AF:

0.673

AC:

24202

AN:

35940

Middle Eastern (MID)

AF:

0.644

AC:

2831

AN:

4396

European-Non Finnish (NFE)

AF:

0.786

AC:

723273

AN:

920626

Other (OTH)

AF:

0.712

AC:

31267

AN:

43942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

10293

20585

30878

41170

51463

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19666

39332

58998

78664

98330

<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:

0.681

AC:

103584

AN:

152044

Hom.:

36363

Cov.:

AF XY:

0.671

AC XY:

49852

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.644

AC:

26692

AN:

41458

American (AMR)

AF:

0.520

AC:

7940

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.666

AC:

2311

AN:

3472

East Asian (EAS)

AF:

0.377

AC:

1944

AN:

5150

South Asian (SAS)

AF:

0.503

AC:

2427

AN:

4826

European-Finnish (FIN)

AF:

0.663

AC:

7024

AN:

10592

Middle Eastern (MID)

AF:

0.699

AC:

204

AN:

292

European-Non Finnish (NFE)

AF:

0.778

AC:

52832

AN:

67950

Other (OTH)

AF:

0.665

AC:

1404

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1596

3192

4788

6384

7980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<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:

0.721

Hom.:

9303

Bravo

AF:

0.667

Asia WGS

AF:

0.427

AC:

1488

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.2

(source)

DANN

Benign

0.73

PhyloP100

-1.2

PromoterAI

0.0013

Neutral

(source)

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over