rs3736168

Variant names:

• chr4-39366463-C-A
• rs3736168
• NM_002913.5:c.-222G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-39366463-C-A
• chr4-39366463-C-G
• chr4-39366463-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002913.5(RFC1):​c.-222G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RFC1 NM_002913.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.757
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.-222G>T		upstream_gene	N/A	NP_002904.3
	RFC1	NM_001204747.2		c.-222G>T		upstream_gene	N/A	NP_001191676.1
	RFC1	NM_001363496.2		c.-222G>T		upstream_gene	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.-222G>T		upstream_gene	N/A	ENSP00000261424.4
	RFC1	ENST00000381897.5	TSL:1	c.-222G>T		upstream_gene	N/A	ENSP00000371321.1
	RFC1	ENST00000418436.5	TSL:1	n.-101G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 321332 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 166786

African (AFR) AF: 0.00 AC: 0 AN: 8002

American (AMR) AF: 0.00 AC: 0 AN: 9314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10154

East Asian (EAS) AF: 0.00 AC: 0 AN: 23126

South Asian (SAS) AF: 0.00 AC: 0 AN: 18572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1600

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 207782

Other (OTH) AF: 0.00 AC: 0 AN: 19076

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.4
DANN	Benign	0.80
PhyloP100		-0.76
PromoterAI		-0.0065	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3736168; hg19: chr4-39368083;