rs2306596

Variant names:

• chr4-39342320-C-A
• rs2306596
• NM_002913.5:c.331+25G>T

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 VariationId 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 rank	MANE	Protein	UniProt
RFC1	NM_002913.5	c.331+25G>T		intron_variant	Intron 4 of 24	ENST00000349703.7	NP_002904.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFC1	ENST00000349703.7	c.331+25G>T		intron_variant	Intron 4 of 24	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

GnomAD2 exomes AF: 0.524 AC: 130149 AN: 248444 AF XY: 0.529

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 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

African (AFR) AF: 0.116 AC: 3815 AN: 33000

American (AMR) AF: 0.632 AC: 27748 AN: 43928

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 13168 AN: 25620

East Asian (EAS) AF: 0.637 AC: 24926 AN: 39116

South Asian (SAS) AF: 0.558 AC: 47434 AN: 85008

European-Finnish (FIN) AF: 0.476 AC: 24998 AN: 52540

Middle Eastern (MID) AF: 0.487 AC: 2771 AN: 5692

European-Non Finnish (NFE) AF: 0.526 AC: 580544 AN: 1103864

Other (OTH) AF: 0.498 AC: 29661 AN: 59554

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

African (AFR) AF: 0.130 AC: 5371 AN: 41450

American (AMR) AF: 0.567 AC: 8662 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1756 AN: 3468

East Asian (EAS) AF: 0.628 AC: 3244 AN: 5162

South Asian (SAS) AF: 0.581 AC: 2798 AN: 4814

European-Finnish (FIN) AF: 0.476 AC: 5021 AN: 10542

Middle Eastern (MID) AF: 0.507 AC: 148 AN: 292

European-Non Finnish (NFE) AF: 0.526 AC: 35727 AN: 67896

Other (OTH) AF: 0.463 AC: 978 AN: 2114

Alfa AF: 0.495 Hom.: 13898

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

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Nov 07, 2021

Genome-Nilou Lab

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	-0.81
CADD	Benign	3.9
DANN	Benign	0.74
PhyloP100		-0.39
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: rs2306596; hg19: chr4-39343940; COSMIC: COSV62900719;