rs9993224

Variant names:

• chr4-39298578-C-T
• rs9993224
• NM_002913.5:c.2808+1443G>A

Variant summary

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

The NM_002913.5(RFC1):​c.2808+1443G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.515 in 151,968 control chromosomes in the GnomAD database, including 21,983 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 0.52 (21983 hom., cov: 32)
• Consequence: RFC1 NM_002913.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.544
• Publications: 10 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 (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFC1	NM_002913.5	c.2808+1443G>A		intron_variant	Intron 21 of 24	ENST00000349703.7	NP_002904.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFC1	ENST00000349703.7	c.2808+1443G>A		intron_variant	Intron 21 of 24	1	NM_002913.5	ENSP00000261424.4
RFC1	ENST00000381897.5	c.2811+1443G>A		intron_variant	Intron 21 of 24	1		ENSP00000371321.1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 78178 AN: 151850 Hom.: 21945 Cov.: 32

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.487

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

GnomAD4 genome AF: 0.515 AC: 78271 AN: 151968 Hom.: 21983 Cov.: 32 AF XY: 0.510 AC XY: 37901 AN XY: 74280

African (AFR) AF: 0.752 AC: 31190 AN: 41480

American (AMR) AF: 0.396 AC: 6046 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1648 AN: 3470

East Asian (EAS) AF: 0.375 AC: 1940 AN: 5168

South Asian (SAS) AF: 0.387 AC: 1865 AN: 4816

European-Finnish (FIN) AF: 0.456 AC: 4793 AN: 10522

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29219 AN: 67944

Other (OTH) AF: 0.488 AC: 1024 AN: 2100

Alfa AF: 0.451 Hom.: 8294

Bravo AF: 0.521

Asia WGS AF: 0.415 AC: 1441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.79
PhyloP100		-0.54
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: rs9993224; hg19: chr4-39300198;