17-1897306-C-T

Variant names:

• chr17-1897306-C-T
• rs5030740
• NM_002945.5:c.*131C>T

Variant summary

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

The ENST00000254719.10(RPA1):​c.*131C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.779 in 675,836 control chromosomes in the GnomAD database, including 207,667 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 0.73 (41882 hom., cov: 31)
  • Exomes 𝑓: 0.79 (165785 hom.)
• Consequence: RPA1 ENST00000254719.10 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0950
• Publications: 27 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000254719.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	NM_002945.5	MANE Select	c.*131C>T		3_prime_UTR	Exon 17 of 17	NP_002936.1
	RPA1	NM_001355120.2		c.*131C>T		3_prime_UTR	Exon 17 of 17	NP_001342049.1
	RPA1	NM_001355121.2		c.*131C>T		3_prime_UTR	Exon 16 of 16	NP_001342050.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	ENST00000254719.10	TSL:1 MANE Select	c.*131C>T		3_prime_UTR	Exon 17 of 17	ENSP00000254719.4
	RPA1	ENST00000573994.1	TSL:2	n.614C>T		non_coding_transcript_exon	Exon 3 of 3
	RPA1	ENST00000574049.1	TSL:5	c.*131C>T		3_prime_UTR	Exon 8 of 8	ENSP00000461466.1

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111312 AN: 151924 Hom.: 41880 Cov.: 31

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.767

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.827

Gnomad SAS AF: 0.673

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.813

Gnomad OTH AF: 0.772

GnomAD4 exome AF: 0.793 AC: 415144 AN: 523794 Hom.: 165785 Cov.: 7 AF XY: 0.788 AC XY: 216028 AN XY: 274032

African (AFR) AF: 0.540 AC: 7267 AN: 13458

American (AMR) AF: 0.760 AC: 14722 AN: 19364

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 11413 AN: 14004

East Asian (EAS) AF: 0.831 AC: 25825 AN: 31094

South Asian (SAS) AF: 0.685 AC: 32408 AN: 47338

European-Finnish (FIN) AF: 0.824 AC: 32513 AN: 39476

Middle Eastern (MID) AF: 0.816 AC: 1746 AN: 2140

European-Non Finnish (NFE) AF: 0.813 AC: 267274 AN: 328802

Other (OTH) AF: 0.782 AC: 21976 AN: 28118

GnomAD4 genome AF: 0.732 AC: 111346 AN: 152042 Hom.: 41882 Cov.: 31 AF XY: 0.735 AC XY: 54629 AN XY: 74322

African (AFR) AF: 0.545 AC: 22574 AN: 41434

American (AMR) AF: 0.767 AC: 11725 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.811 AC: 2813 AN: 3468

East Asian (EAS) AF: 0.827 AC: 4270 AN: 5166

South Asian (SAS) AF: 0.673 AC: 3239 AN: 4812

European-Finnish (FIN) AF: 0.826 AC: 8746 AN: 10588

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.813 AC: 55291 AN: 67976

Other (OTH) AF: 0.762 AC: 1609 AN: 2112

Alfa AF: 0.790 Hom.: 93577

Bravo AF: 0.723

Asia WGS AF: 0.692 AC: 2407 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.7
DANN	Benign	0.70
PhyloP100		0.095
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5030740; hg19: chr17-1800600;