17-1844734-A-G

Position:

• chr17-1844734-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000254719.10(RPA1):​c.272+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.893 in 1,403,766 control chromosomes in the GnomAD database, including 562,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.87 (57335 hom., cov: 31)
  • Exomes 𝑓: 0.90 (504920 hom.)
• Consequence: RPA1 ENST00000254719.10 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.533

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 17-1844734-A-G is Benign according to our data. Variant chr17-1844734-A-G is described in ClinVar as [Benign]. Clinvar id is 2687931.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPA1	NM_002945.5	c.272+48A>G		intron_variant		ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.233+48A>G		intron_variant			NP_001342049.1
RPA1	NM_001355121.2	c.272+48A>G		intron_variant			NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.272+48A>G		intron_variant		1	NM_002945.5	ENSP00000254719	P1
RPA1	ENST00000570451.5	c.233+48A>G		intron_variant		3		ENSP00000459788
RPA1	ENST00000571058.5	c.233+48A>G		intron_variant		4		ENSP00000461733
RPA1	ENST00000571725.1	n.188+48A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.866 AC: 131610 AN: 152016 Hom.: 57292 Cov.: 31

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.825

Gnomad ASJ AF: 0.818

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.930

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.918

Gnomad OTH AF: 0.864

GnomAD3 exomes AF: 0.859 AC: 179444 AN: 208944 Hom.: 77511 AF XY: 0.857 AC XY: 95891 AN XY: 111830

Gnomad AFR exome AF: 0.805

Gnomad AMR exome AF: 0.803

Gnomad ASJ exome AF: 0.826

Gnomad EAS exome AF: 0.791

Gnomad SAS exome AF: 0.736

Gnomad FIN exome AF: 0.928

Gnomad NFE exome AF: 0.919

Gnomad OTH exome AF: 0.869

GnomAD4 exome AF: 0.896 AC: 1121486 AN: 1251632 Hom.: 504920 Cov.: 15 AF XY: 0.891 AC XY: 555040 AN XY: 622610

Gnomad4 AFR exome AF: 0.801

Gnomad4 AMR exome AF: 0.804

Gnomad4 ASJ exome AF: 0.827

Gnomad4 EAS exome AF: 0.749

Gnomad4 SAS exome AF: 0.738

Gnomad4 FIN exome AF: 0.931

Gnomad4 NFE exome AF: 0.923

Gnomad4 OTH exome AF: 0.878

GnomAD4 genome AF: 0.866 AC: 131702 AN: 152134 Hom.: 57335 Cov.: 31 AF XY: 0.863 AC XY: 64217 AN XY: 74394

Gnomad4 AFR AF: 0.806

Gnomad4 AMR AF: 0.826

Gnomad4 ASJ AF: 0.818

Gnomad4 EAS AF: 0.779

Gnomad4 SAS AF: 0.728

Gnomad4 FIN AF: 0.930

Gnomad4 NFE AF: 0.918

Gnomad4 OTH AF: 0.855

Alfa AF: 0.897 Hom.: 106586

Bravo AF: 0.858

Asia WGS AF: 0.720 AC: 2504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 95% of patients studied by a panel of primary immunodeficiencies. Number of patients: 90. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.0
DANN	Benign	0.26

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

Other links and lift over

dbSNP: rs4790827; hg19: chr17-1748028;