Genetic Variant NM_002945.5:c.171G>A (chr17-1844585-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002945.5(RPA1):c.171G>A(p.Met57Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RPA1
NM_002945.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.58

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPA1	NM_002945.5 link	c.171G>A	p.Met57Ile	missense_variant	Exon 4 of 17	ENST00000254719.10	NP_002936.1	P27694
RPA1	NM_001355120.2 link	c.132G>A	p.Met44Ile	missense_variant	Exon 4 of 17		NP_001342049.1
RPA1	NM_001355121.2 link	c.171G>A	p.Met57Ile	missense_variant	Exon 4 of 16		NP_001342050.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RPA1	ENST00000254719.10 link	c.171G>A	p.Met57Ile	missense_variant	Exon 4 of 17	1	NM_002945.5	ENSP00000254719.4	P27694
RPA1	ENST00000570451.5 link	c.132G>A	p.Met44Ile	missense_variant	Exon 4 of 7	3		ENSP00000459788.1	I3L2M5
RPA1	ENST00000571058.5 link	c.132G>A	p.Met44Ile	missense_variant	Exon 4 of 6	4		ENSP00000461733.1	I3L524
RPA1	ENST00000571725.1 link	n.87G>A		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460526

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726396

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.171G>A (p.M57I) alteration is located in exon 4 (coding exon 4) of the RPA1 gene. This alteration results from a G to A substitution at nucleotide position 171, causing the methionine (M) at amino acid position 57 to be replaced by an isoleucine (I). 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

0.98

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;T

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.066

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.3

.;.;M

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.8

.;.;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0060

.;.;D

Sift4G

Pathogenic

0.0

D;D;T

Polyphen

0.86

.;.;P

Vest4

0.87

MutPred

0.90

.;.;Gain of catalytic residue at L62 (P = 0.0244);

MVP

0.73

MPC

0.68

ClinPred

0.96

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.76

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over