NM_002913.5:c.3+1269A>G

Variant names:

• chr4-39364970-T-C
• rs6844176
• NM_002913.5:c.3+1269A>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.3+1269A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 151,796 control chromosomes in the GnomAD database, including 12,980 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 0.38 (12980 hom., cov: 29)
• Consequence: RFC1 NM_002913.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0300
• Publications: 14 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFC1	NM_002913.5	c.3+1269A>G		intron_variant	Intron 1 of 24	ENST00000349703.7	NP_002904.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFC1	ENST00000349703.7	c.3+1269A>G		intron_variant	Intron 1 of 24	1	NM_002913.5	ENSP00000261424.4

Frequencies

GnomAD3 genomes AF: 0.378 AC: 57361 AN: 151678 Hom.: 12977 Cov.: 29

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.491

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.423

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

GnomAD4 genome AF: 0.378 AC: 57365 AN: 151796 Hom.: 12980 Cov.: 29 AF XY: 0.383 AC XY: 28413 AN XY: 74156

African (AFR) AF: 0.126 AC: 5239 AN: 41440

American (AMR) AF: 0.547 AC: 8336 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.491 AC: 1702 AN: 3468

East Asian (EAS) AF: 0.586 AC: 3026 AN: 5168

South Asian (SAS) AF: 0.557 AC: 2683 AN: 4814

European-Finnish (FIN) AF: 0.367 AC: 3842 AN: 10462

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.459 AC: 31149 AN: 67884

Other (OTH) AF: 0.422 AC: 889 AN: 2106

Alfa AF: 0.450 Hom.: 37048

Bravo AF: 0.379

Asia WGS AF: 0.509 AC: 1772 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.3
DANN	Benign	0.58
PhyloP100		-0.030
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6844176; hg19: chr4-39366590;