3-186790133-C-T

Variant names:

• chr3-186790133-C-T
• rs2066500
• NM_002916.5:c.996+9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002916.5(RFC4):​c.996+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,605,322 control chromosomes in the GnomAD database, including 56,171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4952 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51219 hom.)
• Consequence: RFC4 NM_002916.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.82

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]

EIF4A2 (HGNC:3284): (eukaryotic translation initiation factor 4A2) Enables ATP hydrolysis activity. Involved in negative regulation of RNA-directed 5'-3' RNA polymerase activity. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-186790133-C-T is Benign according to our data. Variant chr3-186790133-C-T is described in ClinVar as [Benign]. Clinvar id is 1268726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFC4	NM_002916.5	c.996+9G>A		intron_variant	Intron 10 of 10	ENST00000296273.7	NP_002907.1
RFC4	NM_181573.3	c.996+9G>A		intron_variant	Intron 10 of 10		NP_853551.1
EIF4A2	NM_001967.4	c.*864C>T		downstream_gene_variant		ENST00000323963.10	NP_001958.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFC4	ENST00000296273.7	c.996+9G>A		intron_variant	Intron 10 of 10	1	NM_002916.5	ENSP00000296273.2
EIF4A2	ENST00000323963.10	c.*864C>T		downstream_gene_variant		1	NM_001967.4	ENSP00000326381.5

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35751 AN: 151878 Hom.: 4947 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.284

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.293 AC: 73376 AN: 250628 AF XY: 0.288

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.425

Gnomad ASJ exome AF: 0.214

Gnomad EAS exome AF: 0.399

Gnomad FIN exome AF: 0.398

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.286

GnomAD4 exome AF: 0.259 AC: 375932 AN: 1453326 Hom.: 51219 Cov.: 29 AF XY: 0.259 AC XY: 187280 AN XY: 723394

Gnomad4 AFR exome AF: 0.0989 AC: 3296 AN: 33312

Gnomad4 AMR exome AF: 0.419 AC: 18679 AN: 44606

Gnomad4 ASJ exome AF: 0.219 AC: 5701 AN: 26074

Gnomad4 EAS exome AF: 0.413 AC: 16383 AN: 39648

Gnomad4 SAS exome AF: 0.290 AC: 24875 AN: 85888

Gnomad4 FIN exome AF: 0.393 AC: 21000 AN: 53406

Gnomad4 NFE exome AF: 0.244 AC: 269309 AN: 1104566

Gnomad4 Remaining exome AF: 0.257 AC: 15437 AN: 60072

GnomAD4 genome AF: 0.235 AC: 35770 AN: 151996 Hom.: 4952 Cov.: 32 AF XY: 0.245 AC XY: 18209 AN XY: 74268

Gnomad4 AFR AF: 0.108 AC: 0.108412 AN: 0.108412

Gnomad4 AMR AF: 0.332 AC: 0.33185 AN: 0.33185

Gnomad4 ASJ AF: 0.227 AC: 0.226801 AN: 0.226801

Gnomad4 EAS AF: 0.410 AC: 0.410112 AN: 0.410112

Gnomad4 SAS AF: 0.308 AC: 0.307756 AN: 0.307756

Gnomad4 FIN AF: 0.404 AC: 0.404436 AN: 0.404436

Gnomad4 NFE AF: 0.247 AC: 0.246799 AN: 0.246799

Gnomad4 OTH AF: 0.225 AC: 0.225379 AN: 0.225379

Alfa AF: 0.234 Hom.: 11376

Bravo AF: 0.225

Asia WGS AF: 0.376 AC: 1310 AN: 3478

EpiCase AF: 0.236

EpiControl AF: 0.239

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.0010
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

LitVar

Other links and lift over

dbSNP: rs2066500; hg19: chr3-186507922; COSMIC: COSV56216237; COSMIC: COSV56216237;