17-1853102-A-G

Position:

• chr17-1853102-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002945.5(RPA1):​c.274A>G​(p.Arg92Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPA1 NM_002945.5 missense, splice_region
• Scores: Splicing: ADA: 0.8597
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPA1	NM_002945.5	c.274A>G	p.Arg92Gly	missense_variant, splice_region_variant	5/17	ENST00000254719.10	NP_002936.1
RPA1	NM_001355120.2	c.235A>G	p.Arg79Gly	missense_variant, splice_region_variant	5/17		NP_001342049.1
RPA1	NM_001355121.2	c.274A>G	p.Arg92Gly	missense_variant, splice_region_variant	5/16		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPA1	ENST00000254719.10	c.274A>G	p.Arg92Gly	missense_variant, splice_region_variant	5/17	1	NM_002945.5	ENSP00000254719	P1
RPA1	ENST00000570451.5	c.235A>G	p.Arg79Gly	missense_variant, splice_region_variant	5/7	3		ENSP00000459788
RPA1	ENST00000571058.5	c.235A>G	p.Arg79Gly	missense_variant, splice_region_variant	5/6	4		ENSP00000461733
RPA1	ENST00000571725.1	n.190A>G		splice_region_variant, non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 03, 2022

The c.274A>G (p.R92G) alteration is located in exon 5 (coding exon 5) of the RPA1 gene. This alteration results from a A to G substitution at nucleotide position 274, causing the arginine (R) at amino acid position 92 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.3	.;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-4.5	.;.;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	.;.;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.92	.;.;P
Vest4		0.72
MutPred		0.85		.;.;Loss of MoRF binding (P = 0.018);
MVP		0.80
MPC		0.59
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.84
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.86
dbscSNV1_RF	Benign	0.54
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-1756396;