3-186790031-C-T

Position:

• chr3-186790031-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002916.5(RFC4):​c.1030G>A​(p.Glu344Lys) variant causes a missense change. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RFC4 NM_002916.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.70

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]

RFC4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 3-186790031-C-T is Pathogenic according to our data. Variant chr3-186790031-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3376523.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFC4	NM_002916.5	c.1030G>A	p.Glu344Lys	missense_variant	11/11	ENST00000296273.7	NP_002907.1
RFC4	NM_181573.3	c.1030G>A	p.Glu344Lys	missense_variant	11/11		NP_853551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFC4	ENST00000296273.7	c.1030G>A	p.Glu344Lys	missense_variant	11/11	1	NM_002916.5	ENSP00000296273.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

MORIMOTO-RYU-MALICDAN NEUROMUSCULAR SYNDROME Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.074	T;T;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.5	.;H;H
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.90
MutPred		0.69		.;Gain of ubiquitination at E344 (P = 0.0258);Gain of ubiquitination at E344 (P = 0.0258);
MVP		0.89
MPC		0.34
ClinPred		0.99	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.86
gMVP		0.76

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: chr3-186507820;