17-1830105-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5 link	c.12A>G	p.Gln4Gln	synonymous_variant	Exon 1 of 17	ENST00000254719.10	NP_002936.1	P27694
SMYD4	NM_052928.3 link	c.-392T>C		upstream_gene_variant		ENST00000305513.12	NP_443160.2	Q8IYR2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10 link	c.12A>G	p.Gln4Gln	synonymous_variant	Exon 1 of 17	1	NM_002945.5	ENSP00000254719.4		P27694
SMYD4	ENST00000305513.12 link	c.-392T>C		upstream_gene_variant		1	NM_052928.3	ENSP00000304360.7		Q8IYR2

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

GnomAD3 exomes

AF:

0.662

AC:

14278

AN:

21576

Hom.:

4873

AF XY:

0.667

AC XY:

6386

AN XY:

9570

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 SAS exome

AF:

0.427

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

Gnomad4 AFR exome

AF:

0.638

Gnomad4 AMR exome

AF:

0.473

Gnomad4 ASJ exome

AF:

0.663

Gnomad4 EAS exome

AF:

0.333

Gnomad4 SAS exome

AF:

0.513

Gnomad4 FIN exome

AF:

0.673

Gnomad4 NFE exome

AF:

0.786

Gnomad4 OTH exome

AF:

0.712

GnomAD4 genome

AF:

0.681

AC:

103584

AN:

152044

Hom.:

36363

Cov.:

AF XY:

0.671

AC XY:

49852

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.644

Gnomad4 AMR

AF:

0.520

Gnomad4 ASJ

AF:

0.666

Gnomad4 EAS

AF:

0.377

Gnomad4 SAS

AF:

0.503

Gnomad4 FIN

AF:

0.663

Gnomad4 NFE

AF:

0.778

Gnomad4 OTH

AF:

0.665

Alfa

AF:

0.734

Hom.:

8351

Bravo

AF:

0.667

Asia WGS

AF:

0.427

AC:

1488

AN:

3472

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 67% of patients studied by a panel of primary immunodeficiencies. Number of patients: 64. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.2

DANN

Benign

0.73

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over