1-27894361-T-C

Position:

• chr1-27894361-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002946.5(RPA2):​c.562A>G​(p.Met188Val) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPA2 NM_002946.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

Genes affected

RPA2 (HGNC:10290): (replication protein A2) This gene encodes a 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 RPA complex protects 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. The heterotrimeric complex has two different modes of ssDNA binding, a low-affinity and high-affinity mode, determined by which oligonucleotide/oligosaccharide-binding (OB) domains of the complex are utilized, and differing in the length of DNA bound. This subunit contains a single OB domain that participates in high-affinity DNA binding and also contains a winged helix domain at its carboxy terminus, which interacts with many genome maintenance protein. Post-translational modifications of the RPA complex also plays a role in co-ordinating different damage response pathways. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19544223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPA2	NM_002946.5	c.562A>G	p.Met188Val	missense_variant	7/9	ENST00000373912.8	NP_002937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPA2	ENST00000373912.8	c.562A>G	p.Met188Val	missense_variant	7/9	1	NM_002946.5	ENSP00000363021.3
RPA2	ENST00000313433.11	c.826A>G	p.Met276Val	missense_variant	6/8	1		ENSP00000363015.3
RPA2	ENST00000373909.7	c.586A>G	p.Met196Val	missense_variant	7/9	3		ENSP00000363017.3
RPA2	ENST00000419958.5	c.118A>G	p.Met40Val	missense_variant	2/5	3		ENSP00000413541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 29, 2024

The c.562A>G (p.M188V) alteration is located in exon 7 (coding exon 7) of the RPA2 gene. This alteration results from a A to G substitution at nucleotide position 562, causing the methionine (M) at amino acid position 188 to be replaced by a valine (V). 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	Benign	0.065
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.064	T;T;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.0058
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.59	N;N;N;N
REVEL	Benign	0.092
Sift	Benign	0.60	T;T;T;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.0070	B;.;B;.
Vest4		0.23
MutPred		0.60		Loss of loop (P = 0.1258);.;.;.;
MVP		0.73
MPC		0.26
ClinPred		0.62	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.44

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-28220872;