12-118025769-A-G

Variant names:

• chr12-118025769-A-G
• NM_007370.7:c.604A>G

Variant summary

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

The NM_007370.7(RFC5):​c.604A>G​(p.Met202Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFC5 NM_007370.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31

Genes affected

RFC5 (HGNC:9973): (replication factor C subunit 5) This gene encodes the smallest subunit of the replication factor C complex, which consists of five distinct subunits (140, 40, 38, 37, and 36 kDa) and is required for DNA replication. This subunit interacts with the C-terminal region of proliferating cell nuclear antigen and is required to open and load proliferating cell nuclear antigen onto DNA during S phase. It is a member of the AAA+ (ATPases associated with various cellular activities) ATPase family and forms a core complex with the 38 and 40 kDa subunits that possesses DNA-dependent ATPase activity. A related pseudogene has been identified on chromosome 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFC5	NM_007370.7	c.604A>G	p.Met202Val	missense_variant	Exon 7 of 11	ENST00000454402.7	NP_031396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFC5	ENST00000454402.7	c.604A>G	p.Met202Val	missense_variant	Exon 7 of 11	1	NM_007370.7	ENSP00000408295.2
RFC5	ENST00000392542.6	c.541A>G	p.Met181Val	missense_variant	Exon 8 of 12	2		ENSP00000376325.2
RFC5	ENST00000472603.1	n.118A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.604A>G (p.M202V) alteration is located in exon 7 (coding exon 7) of the RFC5 gene. This alteration results from a A to G substitution at nucleotide position 604, causing the methionine (M) at amino acid position 202 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	0.11
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.072
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.0078	T
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.24
Sift	Benign	0.77	T;T
Sift4G	Benign	0.58	T;.
Polyphen		0.0010	B;.
Vest4		0.83
MutPred		0.50		Gain of methylation at K203 (P = 0.0409);.;
MVP		0.52
MPC		0.40
ClinPred		0.44	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.86

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.

Other links and lift over

hg19: chr12-118463574;