3-186790241-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002916.5(RFC4):ā€‹c.897G>Cā€‹(p.Glu299Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 32)
Exomes š‘“: 0.000062 ( 0 hom. )

Consequence

RFC4
NM_002916.5 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.06
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12860823).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RFC4NM_002916.5 linkc.897G>C p.Glu299Asp missense_variant Exon 10 of 11 ENST00000296273.7 NP_002907.1 P35249-1
RFC4NM_181573.3 linkc.897G>C p.Glu299Asp missense_variant Exon 10 of 11 NP_853551.1 P35249-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RFC4ENST00000296273.7 linkc.897G>C p.Glu299Asp missense_variant Exon 10 of 11 1 NM_002916.5 ENSP00000296273.2 P35249-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152078
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000478
AC:
12
AN:
251176
Hom.:
0
AF XY:
0.0000589
AC XY:
8
AN XY:
135822
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.000106
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000616
AC:
90
AN:
1461222
Hom.:
0
Cov.:
31
AF XY:
0.0000674
AC XY:
49
AN XY:
726952
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:
0.00
Gnomad4 NFE exome
AF:
0.0000765
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152078
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74280
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000675
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Jul 14, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.897G>C (p.E299D) alteration is located in exon 10 (coding exon 9) of the RFC4 gene. This alteration results from a G to C substitution at nucleotide position 897, causing the glutamic acid (E) at amino acid position 299 to be replaced by an aspartic acid (D). 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
0.13
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
9.3
DANN
Benign
0.87
DEOGEN2
Benign
0.016
T;T;T;T
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.30
T;T;.;T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
.;L;L;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.0
N;N;N;N
REVEL
Benign
0.089
Sift
Benign
0.59
T;T;T;T
Sift4G
Benign
0.56
T;T;T;T
Polyphen
0.0070
.;B;B;.
Vest4
0.52
MutPred
0.41
.;Gain of catalytic residue at E299 (P = 0.0707);Gain of catalytic residue at E299 (P = 0.0707);.;
MVP
0.39
MPC
0.049
ClinPred
0.069
T
GERP RS
1.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.54
gMVP
0.53

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.17
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: rs771112894; hg19: chr3-186508030; API