chr17-1894596-G-A

Variant names:

• chr17-1894596-G-A
• rs7503021
• NM_002945.5:c.1660-413G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002945.5(RPA1):​c.1660-413G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 152,244 control chromosomes in the GnomAD database, including 162 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 0.037 (162 hom., cov: 31)
• Consequence: RPA1 NM_002945.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 4 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5	c.1660-413G>A		intron_variant	Intron 15 of 16	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.1621-413G>A		intron_variant	Intron 15 of 16		NP_001342049.1
RPA1	NM_001355121.2	c.1483-413G>A		intron_variant	Intron 14 of 15		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.1660-413G>A		intron_variant	Intron 15 of 16	1	NM_002945.5	ENSP00000254719.4
RPA1	ENST00000574049.1	c.751-413G>A		intron_variant	Intron 6 of 7	5		ENSP00000461466.1
RPA1	ENST00000573994.1	n.292-413G>A		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0372 AC: 5657 AN: 152126 Hom.: 162 Cov.: 31

Gnomad AFR AF: 0.00971

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0360

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0587

Gnomad OTH AF: 0.0282

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0371 AC: 5655 AN: 152244 Hom.: 162 Cov.: 31 AF XY: 0.0357 AC XY: 2654 AN XY: 74430

African (AFR) AF: 0.00968 AC: 402 AN: 41534

American (AMR) AF: 0.0232 AC: 355 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0360 AC: 125 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5188

South Asian (SAS) AF: 0.0164 AC: 79 AN: 4828

European-Finnish (FIN) AF: 0.0536 AC: 568 AN: 10594

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0587 AC: 3994 AN: 68016

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

Alfa AF: 0.0478 Hom.: 279

Bravo AF: 0.0340

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.71
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7503021; hg19: chr17-1797890;