NM_002913.5:c.331+6694C>G

Variant names:

• chr4-39335651-G-C
• rs17288033
• NM_002913.5:c.331+6694C>G

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+6694C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0753 in 152,128 control chromosomes in the GnomAD database, including 569 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 0.075 (569 hom., cov: 32)
• Consequence: RFC1 NM_002913.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630
• Publications: 1 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 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.331+6694C>G		intron	N/A	NP_002904.3
	RFC1	NM_001204747.2		c.331+6694C>G		intron	N/A	NP_001191676.1	P35251-1
	RFC1	NM_001363496.2		c.331+6694C>G		intron	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.331+6694C>G		intron	N/A	ENSP00000261424.4	P35251-2
	RFC1	ENST00000381897.5	TSL:1	c.331+6694C>G		intron	N/A	ENSP00000371321.1	P35251-1
	RFC1	ENST00000418436.5	TSL:1	n.573+6694C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11460 AN: 152008 Hom.: 570 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0761

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0195

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0945

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

GnomAD4 genome AF: 0.0753 AC: 11450 AN: 152128 Hom.: 569 Cov.: 32 AF XY: 0.0760 AC XY: 5652 AN XY: 74352

African (AFR) AF: 0.0197 AC: 817 AN: 41522

American (AMR) AF: 0.0760 AC: 1161 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4818

European-Finnish (FIN) AF: 0.136 AC: 1433 AN: 10558

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7257 AN: 67994

Other (OTH) AF: 0.0935 AC: 197 AN: 2108

Alfa AF: 0.0891 Hom.: 92

Bravo AF: 0.0697

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.2
DANN	Benign	0.40
PhyloP100		0.063
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: rs17288033; hg19: chr4-39337271;