NM_002913.5:c.-222G>A

Variant names:

• chr4-39366463-C-T
• rs3736168
• NM_002913.5:c.-222G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002913.5(RFC1):​c.-222G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 472,634 control chromosomes in the GnomAD database, including 55,970 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.45 (16109 hom., cov: 31)
  • Exomes 𝑓: 0.49 (39861 hom.)
• Consequence: RFC1 NM_002913.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.757
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 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.-222G>A		upstream_gene	N/A	NP_002904.3
	RFC1	NM_001204747.2		c.-222G>A		upstream_gene	N/A	NP_001191676.1	P35251-1
	RFC1	NM_001363496.2		c.-222G>A		upstream_gene	N/A	NP_001350425.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFC1	ENST00000349703.7	TSL:1 MANE Select	c.-222G>A		upstream_gene	N/A	ENSP00000261424.4	P35251-2
	RFC1	ENST00000381897.5	TSL:1	c.-222G>A		upstream_gene	N/A	ENSP00000371321.1	P35251-1
	RFC1	ENST00000418436.5	TSL:1	n.-101G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68724 AN: 151768 Hom.: 16102 Cov.: 31

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.420

Gnomad FIN AF: 0.584

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.505

Gnomad OTH AF: 0.448

GnomAD4 exome AF: 0.495 AC: 158690 AN: 320748 Hom.: 39861 AF XY: 0.493 AC XY: 82107 AN XY: 166504

African (AFR) AF: 0.368 AC: 2942 AN: 7996

American (AMR) AF: 0.425 AC: 3951 AN: 9288

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 4298 AN: 10138

East Asian (EAS) AF: 0.441 AC: 10186 AN: 23090

South Asian (SAS) AF: 0.457 AC: 8455 AN: 18510

European-Finnish (FIN) AF: 0.580 AC: 13735 AN: 23664

Middle Eastern (MID) AF: 0.476 AC: 761 AN: 1600

European-Non Finnish (NFE) AF: 0.507 AC: 105120 AN: 207430

Other (OTH) AF: 0.486 AC: 9242 AN: 19032

GnomAD4 genome AF: 0.453 AC: 68743 AN: 151886 Hom.: 16109 Cov.: 31 AF XY: 0.452 AC XY: 33561 AN XY: 74250

African (AFR) AF: 0.354 AC: 14680 AN: 41414

American (AMR) AF: 0.403 AC: 6157 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1495 AN: 3464

East Asian (EAS) AF: 0.451 AC: 2315 AN: 5130

South Asian (SAS) AF: 0.420 AC: 2022 AN: 4814

European-Finnish (FIN) AF: 0.584 AC: 6177 AN: 10572

Middle Eastern (MID) AF: 0.414 AC: 121 AN: 292

European-Non Finnish (NFE) AF: 0.505 AC: 34287 AN: 67900

Other (OTH) AF: 0.449 AC: 948 AN: 2112

Alfa AF: 0.470 Hom.: 2098

Bravo AF: 0.436

Asia WGS AF: 0.480 AC: 1668 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.3
DANN	Benign	0.90
PhyloP100		-0.76
PromoterAI		-0.24	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3736168; hg19: chr4-39368083; COSMIC: COSV62899151;