chr17-1897895-C-T

Variant names:

• chr17-1897895-C-T
• rs1131636
• NM_002945.5:c.*720C>T

Variant summary

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

The NM_002945.5(RPA1):​c.*720C>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 0.52 in 152,500 control chromosomes in the GnomAD database, including 21,434 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 0.52 (21373 hom., cov: 33)
  • Exomes 𝑓: 0.57 (61 hom.)
• Consequence: RPA1 NM_002945.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63
• Publications: 35 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=-0.59).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA1	NM_002945.5	MANE Select	c.*720C>T		3_prime_UTR	Exon 17 of 17	NP_002936.1
	RPA1	NM_001355120.2		c.*720C>T		3_prime_UTR	Exon 17 of 17	NP_001342049.1
	RPA1	NM_001355121.2		c.*720C>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.*720C>T		3_prime_UTR	Exon 17 of 17	ENSP00000254719.4
	RPA1	ENST00000574049.1	TSL:5	c.*720C>T		3_prime_UTR	Exon 8 of 8	ENSP00000461466.1

Frequencies

GnomAD3 genomes AF: 0.520 AC: 79076 AN: 151984 Hom.: 21376 Cov.: 33

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.574

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.542

GnomAD4 exome AF: 0.570 AC: 227 AN: 398 Hom.: 61 Cov.: 0 AF XY: 0.573 AC XY: 134 AN XY: 234

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.563 AC: 216 AN: 384

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.875 AC: 7 AN: 8

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.520 AC: 79085 AN: 152102 Hom.: 21373 Cov.: 33 AF XY: 0.518 AC XY: 38500 AN XY: 74358

African (AFR) AF: 0.380 AC: 15767 AN: 41472

American (AMR) AF: 0.542 AC: 8284 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 1989 AN: 3468

East Asian (EAS) AF: 0.550 AC: 2843 AN: 5166

South Asian (SAS) AF: 0.390 AC: 1882 AN: 4830

European-Finnish (FIN) AF: 0.564 AC: 5968 AN: 10580

Middle Eastern (MID) AF: 0.558 AC: 164 AN: 294

European-Non Finnish (NFE) AF: 0.595 AC: 40482 AN: 67984

Other (OTH) AF: 0.534 AC: 1130 AN: 2116

Alfa AF: 0.567 Hom.: 76413

Bravo AF: 0.517

Asia WGS AF: 0.403 AC: 1403 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		2.6
Mutation Taster		=99/1	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: rs1131636; hg19: chr17-1801189; COSMIC: COSV54613089; COSMIC: COSV54613089;