3-186790180-A-C

Variant summary

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

The NM_002916.5(RFC4):ā€‹c.958T>Gā€‹(p.Ser320Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

RFC4
NM_002916.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46
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=0.12745193).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RFC4NM_002916.5 linkc.958T>G p.Ser320Ala missense_variant Exon 10 of 11 ENST00000296273.7 NP_002907.1 P35249-1
RFC4NM_181573.3 linkc.958T>G p.Ser320Ala 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.958T>G p.Ser320Ala missense_variant Exon 10 of 11 1 NM_002916.5 ENSP00000296273.2 P35249-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152166
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:
0.000193
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
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461648
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727140
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Apr 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.958T>G (p.S320A) alteration is located in exon 10 (coding exon 9) of the RFC4 gene. This alteration results from a T to G substitution at nucleotide position 958, causing the serine (S) at amino acid position 320 to be replaced by an alanine (A). 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
0.12
BayesDel_addAF
Benign
-0.068
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
16
DANN
Uncertain
0.97
DEOGEN2
Benign
0.022
T;T;T;T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.53
D
LIST_S2
Benign
0.78
T;T;.;T
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-0.95
T
MutationAssessor
Uncertain
2.5
.;M;M;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.9
N;N;N;N
REVEL
Benign
0.20
Sift
Benign
0.23
T;T;T;D
Sift4G
Benign
0.35
T;T;T;T
Polyphen
0.078
.;B;B;.
Vest4
0.39
MutPred
0.48
.;Loss of ubiquitination at K322 (P = 0.0418);Loss of ubiquitination at K322 (P = 0.0418);.;
MVP
0.37
MPC
0.070
ClinPred
0.65
D
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.15
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs199928937; hg19: chr3-186507969; API