chr3-186791727-C-G

Variant summary

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

The ENST00000296273.7(RFC4):ā€‹c.799G>Cā€‹(p.Gly267Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,948 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

RFC4
ENST00000296273.7 missense, splice_region

Scores

8
6
5
Splicing: ADA: 0.9932
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.33
Variant links:
Genes affected
RFC4 (HGNC:9972): (replication factor C subunit 4) The elongation of primed DNA templates by DNA polymerase delta and DNA polymerase epsilon requires the accessory proteins proliferating cell nuclear antigen (PCNA) and replication factor C (RFC). RFC, also named activator 1, is a protein complex consisting of five distinct subunits of 140, 40, 38, 37, and 36 kD. This gene encodes the 37 kD subunit. This subunit forms a core complex with the 36 and 40 kDa subunits. The core complex possesses DNA-dependent ATPase activity, which was found to be stimulated by PCNA in an in vitro system. Alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons MANE Protein UniProt
RFC4NM_002916.5 linkuse as main transcriptc.799G>C p.Gly267Arg missense_variant, splice_region_variant 8/11 ENST00000296273.7 NP_002907.1
RFC4NM_181573.3 linkuse as main transcriptc.799G>C p.Gly267Arg missense_variant, splice_region_variant 8/11 NP_853551.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RFC4ENST00000296273.7 linkuse as main transcriptc.799G>C p.Gly267Arg missense_variant, splice_region_variant 8/111 NM_002916.5 ENSP00000296273 P1P35249-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251410
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135874
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1460666
Hom.:
0
Cov.:
28
AF XY:
0.00000550
AC XY:
4
AN XY:
726710
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152282
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 14, 2023The c.799G>C (p.G267R) alteration is located in exon 8 (coding exon 7) of the RFC4 gene. This alteration results from a G to C substitution at nucleotide position 799, causing the glycine (G) at amino acid position 267 to be replaced by an arginine (R). 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
0.97
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.25
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.073
T;T;T;T
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.81
T;D;.;D
M_CAP
Uncertain
0.18
D
MetaRNN
Uncertain
0.72
D;D;D;D
MetaSVM
Uncertain
0.34
D
MutationAssessor
Pathogenic
3.6
.;H;H;.
MutationTaster
Benign
0.55
D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-2.2
N;D;D;D
REVEL
Uncertain
0.60
Sift
Benign
0.041
D;D;D;D
Sift4G
Uncertain
0.012
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
0.83
MutPred
0.72
Loss of catalytic residue at V268 (P = 0.031);Loss of catalytic residue at V268 (P = 0.031);Loss of catalytic residue at V268 (P = 0.031);.;
MVP
0.92
MPC
0.35
ClinPred
0.95
D
GERP RS
5.7
Varity_R
0.92
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.92
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs187852064; hg19: chr3-186509516; API