rs2066786

Variant names:

• chr4-39300409-T-C
• rs2066786
• NM_002913.5:c.2541A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-39300409-T-C
• chr4-39300409-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002913.5(RFC1):​c.2541A>G​(p.Pro847Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,611,612 control chromosomes in the GnomAD database, including 253,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18661 hom., cov: 32)
  • Exomes 𝑓: 0.56 (234752 hom.)
• Consequence: RFC1 NM_002913.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.95
• Publications: 28 publications found

Genes affected

RFC1 (HGNC:9969): (replication factor C subunit 1) This gene encodes the large subunit of replication factor C, a five subunit DNA polymerase accessory protein, which is a DNA-dependent ATPase required for eukaryotic DNA replication and repair. The large subunit acts as an activator of DNA polymerases, binds to the 3' end of primers, and promotes coordinated synthesis of both strands. It may also have a role in telomere stability. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Mar 2011]

RFC1 Gene-Disease associations (from GenCC):

• cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• cerebellar ataxia, neuropathy, and vestibular areflexia syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 4-39300409-T-C is Benign according to our data. Variant chr4-39300409-T-C is described in ClinVar as Benign. ClinVar VariationId is 1327949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.95 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002913.5. 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
	RFC1	NM_002913.5	MANE Select	c.2541A>G	p.Pro847Pro	synonymous	Exon 20 of 25	NP_002904.3
	RFC1	NM_001204747.2		c.2544A>G	p.Pro848Pro	synonymous	Exon 20 of 25	NP_001191676.1	P35251-1
	RFC1	NM_001363496.2		c.2466A>G	p.Pro822Pro	synonymous	Exon 19 of 24	NP_001350425.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFC1	ENST00000349703.7	TSL:1 MANE Select	c.2541A>G	p.Pro847Pro	synonymous	Exon 20 of 25	ENSP00000261424.4	P35251-2
	RFC1	ENST00000381897.5	TSL:1	c.2544A>G	p.Pro848Pro	synonymous	Exon 20 of 25	ENSP00000371321.1	P35251-1
	RFC1	ENST00000906184.1		c.2544A>G	p.Pro848Pro	synonymous	Exon 20 of 25	ENSP00000576243.1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68910 AN: 151892 Hom.: 18663 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.484

GnomAD2 exomes AF: 0.558 AC: 140006 AN: 250688 AF XY: 0.565

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.660

Gnomad ASJ exome AF: 0.532

Gnomad EAS exome AF: 0.655

Gnomad FIN exome AF: 0.548

Gnomad NFE exome AF: 0.568

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.562 AC: 819854 AN: 1459602 Hom.: 234752 Cov.: 36 AF XY: 0.564 AC XY: 409464 AN XY: 726176

African (AFR) AF: 0.123 AC: 4117 AN: 33396

American (AMR) AF: 0.645 AC: 28810 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 14077 AN: 26120

East Asian (EAS) AF: 0.644 AC: 25549 AN: 39690

South Asian (SAS) AF: 0.593 AC: 51121 AN: 86164

European-Finnish (FIN) AF: 0.554 AC: 29571 AN: 53408

Middle Eastern (MID) AF: 0.521 AC: 2994 AN: 5746

European-Non Finnish (NFE) AF: 0.568 AC: 631004 AN: 1110106

Other (OTH) AF: 0.541 AC: 32611 AN: 60326

GnomAD4 genome AF: 0.453 AC: 68904 AN: 152010 Hom.: 18661 Cov.: 32 AF XY: 0.459 AC XY: 34083 AN XY: 74296

African (AFR) AF: 0.139 AC: 5768 AN: 41468

American (AMR) AF: 0.583 AC: 8909 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 1835 AN: 3470

East Asian (EAS) AF: 0.635 AC: 3283 AN: 5170

South Asian (SAS) AF: 0.615 AC: 2951 AN: 4800

European-Finnish (FIN) AF: 0.545 AC: 5751 AN: 10560

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.570 AC: 38735 AN: 67954

Other (OTH) AF: 0.483 AC: 1018 AN: 2106

Alfa AF: 0.526 Hom.: 34005

Bravo AF: 0.441

Asia WGS AF: 0.577 AC: 2009 AN: 3478

EpiCase AF: 0.570

EpiControl AF: 0.571

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (1)
-	-	1	not provided (1)
-	-	1	RFC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.5
DANN	Benign	0.59
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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

Other links and lift over

dbSNP: rs2066786; hg19: chr4-39302029; COSMIC: COSV62898407; COSMIC: COSV62898407;