rs2306596

Positions:

• chr4-39342320-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002913.5(RFC1):​c.331+25G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 1,600,238 control chromosomes in the GnomAD database, including 217,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (16258 hom., cov: 31)
  • Exomes 𝑓: 0.52 (201347 hom.)
• Consequence: RFC1 NM_002913.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.394

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-39342320-C-A is Benign according to our data. Variant chr4-39342320-C-A is described in ClinVar as [Benign]. Clinvar id is 1327950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFC1	NM_002913.5	c.331+25G>T		intron_variant		ENST00000349703.7	NP_002904.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFC1	ENST00000349703.7	c.331+25G>T		intron_variant		1	NM_002913.5	ENSP00000261424.4

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64208 AN: 151798 Hom.: 16255 Cov.: 31

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.476

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.463

GnomAD3 exomes AF: 0.524 AC: 130149 AN: 248444 Hom.: 35997 AF XY: 0.529 AC XY: 71034 AN XY: 134236

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.645

Gnomad ASJ exome AF: 0.509

Gnomad EAS exome AF: 0.645

Gnomad SAS exome AF: 0.563

Gnomad FIN exome AF: 0.472

Gnomad NFE exome AF: 0.526

Gnomad OTH exome AF: 0.529

GnomAD4 exome AF: 0.521 AC: 755065 AN: 1448322 Hom.: 201347 Cov.: 32 AF XY: 0.523 AC XY: 376993 AN XY: 720422

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.632

Gnomad4 ASJ exome AF: 0.514

Gnomad4 EAS exome AF: 0.637

Gnomad4 SAS exome AF: 0.558

Gnomad4 FIN exome AF: 0.476

Gnomad4 NFE exome AF: 0.526

Gnomad4 OTH exome AF: 0.498

GnomAD4 genome AF: 0.423 AC: 64208 AN: 151916 Hom.: 16258 Cov.: 31 AF XY: 0.429 AC XY: 31864 AN XY: 74258

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.567

Gnomad4 ASJ AF: 0.506

Gnomad4 EAS AF: 0.628

Gnomad4 SAS AF: 0.581

Gnomad4 FIN AF: 0.476

Gnomad4 NFE AF: 0.526

Gnomad4 OTH AF: 0.463

Alfa AF: 0.500 Hom.: 10188

Bravo AF: 0.417

Asia WGS AF: 0.556 AC: 1934 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.9
DANN	Benign	0.74

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: rs2306596; hg19: chr4-39343940; COSMIC: COSV62900719;