4-39335333-A-G

Variant names:

• chr4-39335333-A-G
• rs3796517
• NM_002913.5:c.331+7012T>C

Variant summary

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

The NM_002913.5(RFC1):​c.331+7012T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 152,000 control chromosomes in the GnomAD database, including 8,045 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 0.32 (8045 hom., cov: 31)
• Consequence: RFC1 NM_002913.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0350
• Publications: 7 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=-0.73).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.348 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFC1	NM_002913.5	MANE Select	c.331+7012T>C		intron	N/A	NP_002904.3
	RFC1	NM_001204747.2		c.331+7012T>C		intron	N/A	NP_001191676.1
	RFC1	NM_001363496.2		c.331+7012T>C		intron	N/A	NP_001350425.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFC1	ENST00000349703.7	TSL:1 MANE Select	c.331+7012T>C		intron	N/A	ENSP00000261424.4
	RFC1	ENST00000381897.5	TSL:1	c.331+7012T>C		intron	N/A	ENSP00000371321.1
	RFC1	ENST00000418436.5	TSL:1	n.573+7012T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48767 AN: 151882 Hom.: 8041 Cov.: 31

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.309

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.321 AC: 48780 AN: 152000 Hom.: 8045 Cov.: 31 AF XY: 0.319 AC XY: 23674 AN XY: 74284

African (AFR) AF: 0.280 AC: 11617 AN: 41478

American (AMR) AF: 0.275 AC: 4210 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1242 AN: 3462

East Asian (EAS) AF: 0.181 AC: 937 AN: 5168

South Asian (SAS) AF: 0.312 AC: 1502 AN: 4814

European-Finnish (FIN) AF: 0.408 AC: 4300 AN: 10536

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.352 AC: 23916 AN: 67940

Other (OTH) AF: 0.305 AC: 645 AN: 2114

Alfa AF: 0.344 Hom.: 4756

Bravo AF: 0.308

Asia WGS AF: 0.233 AC: 810 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.5
DANN	Benign	0.89
PhyloP100		0.035
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: rs3796517; hg19: chr4-39336953;