chr12-118031188-G-T

Variant names:

• chr12-118031188-G-T
• NM_007370.7:c.933G>T

Variant summary

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

The NM_007370.7(RFC5):​c.933G>T​(p.Arg311Ser) 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 pathogenic outcome for this variant. 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: -0.273

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFC5	NM_007370.7	c.933G>T	p.Arg311Ser	missense_variant	Exon 11 of 11	ENST00000454402.7	NP_031396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFC5	ENST00000454402.7	c.933G>T	p.Arg311Ser	missense_variant	Exon 11 of 11	1	NM_007370.7	ENSP00000408295.2
RFC5	ENST00000392542.6	c.870G>T	p.Arg290Ser	missense_variant	Exon 12 of 12	2		ENSP00000376325.2
RFC5	ENST00000543153.1	n.269G>T		non_coding_transcript_exon_variant	Exon 4 of 6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.933G>T (p.R311S) alteration is located in exon 11 (coding exon 11) of the RFC5 gene. This alteration results from a G to T substitution at nucleotide position 933, causing the arginine (R) at amino acid position 311 to be replaced by a serine (S). 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	0.80
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.57	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D;T
Sift4G	Benign	0.089	T;.
Polyphen		0.93	P;.
Vest4		0.87
MutPred		0.70		Gain of catalytic residue at V314 (P = 0.0155);.;
MVP		0.60
MPC		0.84
ClinPred		1.0	D
GERP RS		-2.0
Varity_R		0.94
gMVP		0.92

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: chr12-118468993;