4-39295580-G-A

Variant names:

• chr4-39295580-G-A
• rs2306597
• NM_002913.5:c.2954+34C>T

Variant summary

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

The NM_002913.5(RFC1):​c.2954+34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,542,264 control chromosomes in the GnomAD database, including 30,292 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 0.17 (2461 hom., cov: 32)
  • Exomes 𝑓: 0.20 (27831 hom.)
• Consequence: RFC1 NM_002913.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.383
• Publications: 21 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: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFC1	NM_002913.5	c.2954+34C>T		intron_variant	Intron 22 of 24	ENST00000349703.7	NP_002904.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFC1	ENST00000349703.7	c.2954+34C>T		intron_variant	Intron 22 of 24	1	NM_002913.5	ENSP00000261424.4
RFC1	ENST00000381897.5	c.2957+34C>T		intron_variant	Intron 22 of 24	1		ENSP00000371321.1
RFC1	ENST00000510783.5	n.169+34C>T		intron_variant	Intron 2 of 4	3

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26331 AN: 151750 Hom.: 2460 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.0664

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.183 AC: 40399 AN: 220356 AF XY: 0.189

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.0610

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.196 AC: 272166 AN: 1390396 Hom.: 27831 Cov.: 26 AF XY: 0.197 AC XY: 135438 AN XY: 687164

African (AFR) AF: 0.118 AC: 3706 AN: 31414

American (AMR) AF: 0.130 AC: 4820 AN: 37050

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 4231 AN: 23858

East Asian (EAS) AF: 0.0665 AC: 2525 AN: 37978

South Asian (SAS) AF: 0.219 AC: 16714 AN: 76192

European-Finnish (FIN) AF: 0.235 AC: 12217 AN: 51998

Middle Eastern (MID) AF: 0.184 AC: 1011 AN: 5504

European-Non Finnish (NFE) AF: 0.202 AC: 216064 AN: 1069098

Other (OTH) AF: 0.190 AC: 10878 AN: 57304

GnomAD4 genome AF: 0.173 AC: 26331 AN: 151868 Hom.: 2461 Cov.: 32 AF XY: 0.175 AC XY: 12954 AN XY: 74190

African (AFR) AF: 0.119 AC: 4924 AN: 41418

American (AMR) AF: 0.150 AC: 2287 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 636 AN: 3468

East Asian (EAS) AF: 0.0664 AC: 343 AN: 5166

South Asian (SAS) AF: 0.197 AC: 949 AN: 4814

European-Finnish (FIN) AF: 0.251 AC: 2641 AN: 10506

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14030 AN: 67924

Other (OTH) AF: 0.165 AC: 347 AN: 2098

Alfa AF: 0.188 Hom.: 5738

Bravo AF: 0.162

Asia WGS AF: 0.135 AC: 470 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.066
DANN	Benign	0.79
PhyloP100		-0.38
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

Other links and lift over

dbSNP: rs2306597; hg19: chr4-39297200; COSMIC: COSV62899362; COSMIC: COSV62899362;