3-186790349-C-A

Variant names:

• chr3-186790349-C-A
• rs76048542
• NM_002916.5:c.859G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002916.5(RFC4):​c.859G>T​(p.Asp287Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D287H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFC4 NM_002916.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.58
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002916.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFC4	NM_002916.5	MANE Select	c.859G>T	p.Asp287Tyr	missense	Exon 9 of 11	NP_002907.1	P35249-1
	RFC4	NM_181573.3		c.859G>T	p.Asp287Tyr	missense	Exon 9 of 11	NP_853551.1	P35249-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFC4	ENST00000296273.7	TSL:1 MANE Select	c.859G>T	p.Asp287Tyr	missense	Exon 9 of 11	ENSP00000296273.2	P35249-1
	RFC4	ENST00000392481.6	TSL:5	c.859G>T	p.Asp287Tyr	missense	Exon 9 of 11	ENSP00000376272.2	P35249-1
	RFC4	ENST00000928091.1		c.859G>T	p.Asp287Tyr	missense	Exon 9 of 11	ENSP00000598150.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000424 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.6
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.26
Sift	Benign	0.045	D
Sift4G	Uncertain	0.043	D
Polyphen		0.90	P
Vest4		0.67
MutPred		0.50		Loss of disorder (P = 0.083)
MVP		0.62
MPC		0.29
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.66
gMVP		0.63
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76048542; hg19: chr3-186508138;