17-1857085-A-G

Variant names:

• chr17-1857085-A-G
• rs11867830
• NM_002945.5:c.361+3896A>G

Variant summary

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

The NM_002945.5(RPA1):​c.361+3896A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 151,966 control chromosomes in the GnomAD database, including 3,187 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 0.19 (3187 hom., cov: 32)
• Consequence: RPA1 NM_002945.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.675
• Publications: 6 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), PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.394 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	NM_002945.5	MANE Select	c.361+3896A>G		intron	N/A	NP_002936.1	P27694
	RPA1	NM_001355120.2		c.322+3896A>G		intron	N/A	NP_001342049.1
	RPA1	NM_001355121.2		c.361+3896A>G		intron	N/A	NP_001342050.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	ENST00000254719.10	TSL:1 MANE Select	c.361+3896A>G		intron	N/A	ENSP00000254719.4	P27694
	RPA1	ENST00000852058.1		c.502+3896A>G		intron	N/A	ENSP00000522117.1
	RPA1	ENST00000852055.1		c.454+3896A>G		intron	N/A	ENSP00000522114.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29540 AN: 151850 Hom.: 3185 Cov.: 32

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.115

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.307

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.200

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

GnomAD4 genome AF: 0.195 AC: 29558 AN: 151966 Hom.: 3187 Cov.: 32 AF XY: 0.203 AC XY: 15046 AN XY: 74262

African (AFR) AF: 0.186 AC: 7730 AN: 41488

American (AMR) AF: 0.244 AC: 3719 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 762 AN: 3472

East Asian (EAS) AF: 0.409 AC: 2110 AN: 5162

South Asian (SAS) AF: 0.307 AC: 1479 AN: 4816

European-Finnish (FIN) AF: 0.258 AC: 2711 AN: 10488

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10457 AN: 67970

Other (OTH) AF: 0.198 AC: 416 AN: 2106

Alfa AF: 0.170 Hom.: 8330

Bravo AF: 0.193

Asia WGS AF: 0.332 AC: 1146 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.3
DANN	Benign	0.27
PhyloP100		0.68
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11867830;

hg19: chr17-1760379;