17-1830105-A-G

Variant names:

• chr17-1830105-A-G
• rs5030749
• NM_002945.5:c.12A>G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.23

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]

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]

ACMG classification

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	c.12A>G	p.Gln4Gln	synonymous_variant	Exon 1 of 17	ENST00000254719.10	NP_002936.1
RPA1	NM_001355121.2	c.12A>G	p.Gln4Gln	synonymous_variant	Exon 1 of 16		NP_001342050.1
RPA1	NM_001355120.2	c.-36A>G		5_prime_UTR_variant	Exon 1 of 17		NP_001342049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.12A>G	p.Gln4Gln	synonymous_variant	Exon 1 of 17	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000570451	c.-36A>G		5_prime_UTR_variant	Exon 1 of 7	3		ENSP00000459788.1
SMYD4	ENST00000571854.5	c.-13+488T>C		intron_variant	Intron 1 of 4	4		ENSP00000461089.1
RPA1	ENST00000571058.5	c.-7+205A>G		intron_variant	Intron 1 of 5	4		ENSP00000461733.1

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103513 AN: 151928 Hom.: 36340 Cov.: 31

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

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.: 50 AF XY: 0.754 AC XY: 391088 AN XY: 518374

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.: 31 AF XY: 0.671 AC XY: 49852 AN XY: 74326

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

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 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

Other links and lift over

dbSNP: rs5030749; hg19: chr17-1733399; COSMIC: COSV54609521; COSMIC: COSV54609521;