17-1897306-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000254719.10(RPA1):​c.*131C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

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>A		3_prime_UTR	Exon 17 of 17	NP_002936.1
	RPA1	NM_001355120.2		c.*131C>A		3_prime_UTR	Exon 17 of 17	NP_001342049.1
	RPA1	NM_001355121.2		c.*131C>A		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>A		3_prime_UTR	Exon 17 of 17	ENSP00000254719.4
	RPA1	ENST00000573994.1	TSL:2	n.614C>A		non_coding_transcript_exon	Exon 3 of 3
	RPA1	ENST00000574049.1	TSL:5	c.*131C>A		3_prime_UTR	Exon 8 of 8	ENSP00000461466.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 524344 Hom.: 0 Cov.: 7 AF XY: 0.00 AC XY: 0 AN XY: 274318

African (AFR) AF: 0.00 AC: 0 AN: 13478

American (AMR) AF: 0.00 AC: 0 AN: 19386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14014

East Asian (EAS) AF: 0.00 AC: 0 AN: 31124

South Asian (SAS) AF: 0.00 AC: 0 AN: 47362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2148

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 329174

Other (OTH) AF: 0.00 AC: 0 AN: 28152

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.0
DANN	Benign	0.67
PhyloP100		0.095

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;