chr4-39287853-A-G

Variant names:

• chr4-39287853-A-G
• rs1057807
• NM_002913.5:c.*908T>C

Variant summary

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

The NM_002913.5(RFC1):​c.*908T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 151,980 control chromosomes in the GnomAD database, including 23,247 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 0.53 (23245 hom., cov: 31)
  • Exomes 𝑓: 0.44 (2 hom.)
• Consequence: RFC1 NM_002913.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.464
• Publications: 18 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 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.*908T>C		3_prime_UTR	Exon 25 of 25	NP_002904.3
	RFC1	NM_001204747.2		c.*908T>C		3_prime_UTR	Exon 25 of 25	NP_001191676.1
	RFC1	NM_001363496.2		c.*908T>C		3_prime_UTR	Exon 24 of 24	NP_001350425.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFC1	ENST00000349703.7	TSL:1 MANE Select	c.*908T>C		3_prime_UTR	Exon 25 of 25	ENSP00000261424.4
	RFC1	ENST00000381897.5	TSL:1	c.*908T>C		3_prime_UTR	Exon 25 of 25	ENSP00000371321.1
	RFC1	ENST00000906184.1		c.*908T>C		3_prime_UTR	Exon 25 of 25	ENSP00000576243.1

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79929 AN: 151846 Hom.: 23205 Cov.: 31

Gnomad AFR AF: 0.788

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.456

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.501

GnomAD4 exome AF: 0.438 AC: 7 AN: 16 Hom.: 2 Cov.: 0 AF XY: 0.429 AC XY: 6 AN XY: 14

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.417 AC: 5 AN: 12

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.527 AC: 80030 AN: 151964 Hom.: 23245 Cov.: 31 AF XY: 0.521 AC XY: 38689 AN XY: 74264

African (AFR) AF: 0.788 AC: 32677 AN: 41444

American (AMR) AF: 0.401 AC: 6117 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1647 AN: 3468

East Asian (EAS) AF: 0.379 AC: 1958 AN: 5160

South Asian (SAS) AF: 0.391 AC: 1881 AN: 4814

European-Finnish (FIN) AF: 0.456 AC: 4818 AN: 10570

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.432 AC: 29323 AN: 67942

Other (OTH) AF: 0.502 AC: 1060 AN: 2110

Alfa AF: 0.459 Hom.: 21503

Bravo AF: 0.535

Asia WGS AF: 0.430 AC: 1495 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.1
DANN	Benign	0.41
PhyloP100		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs1057807; hg19: chr4-39289473;