rs76048542

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-186790349-C-G
• chr3-186790349-C-A
• chr3-186790349-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002916.5(RFC4):​c.859G>C​(p.Asp287His) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RFC4 NM_002916.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3549782).

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>C	p.Asp287His	missense	Exon 9 of 11	NP_002907.1	P35249-1
	RFC4	NM_181573.3		c.859G>C	p.Asp287His	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>C	p.Asp287His	missense	Exon 9 of 11	ENSP00000296273.2	P35249-1
	RFC4	ENST00000392481.6	TSL:5	c.859G>C	p.Asp287His	missense	Exon 9 of 11	ENSP00000376272.2	P35249-1
	RFC4	ENST00000928091.1		c.859G>C	p.Asp287His	missense	Exon 9 of 11	ENSP00000598150.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251442 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461644 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727152

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111798

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.6
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.022	D
Polyphen		0.52	P
Vest4		0.59
MVP		0.51
MPC		0.25
ClinPred		0.72	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.58
gMVP		0.55
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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;