chr4-39312209-T-C

Variant names:

• chr4-39312209-T-C
• rs2381375
• NM_002913.5:c.1383+543A>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.1383+543A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 152,058 control chromosomes in the GnomAD database, including 16,726 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 0.47 (16726 hom., cov: 32)
• Consequence: RFC1 NM_002913.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.70
• Publications: 13 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFC1	NM_002913.5	c.1383+543A>G		intron_variant	Intron 11 of 24	ENST00000349703.7	NP_002904.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFC1	ENST00000349703.7	c.1383+543A>G		intron_variant	Intron 11 of 24	1	NM_002913.5	ENSP00000261424.4
RFC1	ENST00000381897.5	c.1383+543A>G		intron_variant	Intron 11 of 24	1		ENSP00000371321.1
RFC1	ENST00000504554.1	c.279+543A>G		intron_variant	Intron 2 of 4	4		ENSP00000422129.1
RFC1	ENST00000502706.1	n.21+543A>G		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70812 AN: 151940 Hom.: 16696 Cov.: 32

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.445

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.453

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

GnomAD4 genome AF: 0.466 AC: 70893 AN: 152058 Hom.: 16726 Cov.: 32 AF XY: 0.464 AC XY: 34478 AN XY: 74322

African (AFR) AF: 0.470 AC: 19478 AN: 41446

American (AMR) AF: 0.383 AC: 5859 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1716 AN: 3472

East Asian (EAS) AF: 0.372 AC: 1928 AN: 5180

South Asian (SAS) AF: 0.416 AC: 2002 AN: 4818

European-Finnish (FIN) AF: 0.556 AC: 5882 AN: 10574

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.478 AC: 32521 AN: 67966

Other (OTH) AF: 0.454 AC: 959 AN: 2112

Alfa AF: 0.459 Hom.: 8089

Bravo AF: 0.453

Asia WGS AF: 0.415 AC: 1442 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.016
DANN	Benign	0.53
PhyloP100		-2.7
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: rs2381375; hg19: chr4-39313829;