Genetic Variant NM_002913.5:c.2955-607C>T (chr4-39292459-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002913.5(RFC1):c.2955-607C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 152,122 control chromosomes in the GnomAD database, including 173 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 0.040 ( 173 hom., cov: 32)

Consequence

RFC1
NM_002913.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0530

Publications

1 publications found

Variant links:

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

RFC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFC1	NM_002913.5 link	c.2955-607C>T		intron_variant	Intron 22 of 24	ENST00000349703.7	NP_002904.3	P35251-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RFC1	ENST00000349703.7 link	c.2955-607C>T	intron_variant	Intron 22 of 24	1	NM_002913.5	ENSP00000261424.4	P35251-2
RFC1	ENST00000381897.5 link	c.2958-607C>T	intron_variant	Intron 22 of 24	1		ENSP00000371321.1	P35251-1
RFC1	ENST00000510783.5 link	n.170-607C>T	intron_variant	Intron 2 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0397

AC:

6028

AN:

152004

Hom.:

173

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.196

Gnomad AMR

AF:

0.0382

Gnomad ASJ

AF:

0.0666

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0222

Gnomad FIN

AF:

0.0552

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0563

Gnomad OTH

AF:

0.0406

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

GnomAD4 genome

AF:

0.0396

AC:

6025

AN:

152122

Hom.:

173

Cov.:

AF XY:

0.0385

AC XY:

2860

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0100

AC:

417

AN:

41494

American (AMR)

AF:

0.0382

AC:

583

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0666

AC:

231

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0224

AC:

108

AN:

4818

European-Finnish (FIN)

AF:

0.0552

AC:

583

AN:

10564

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0562

AC:

3823

AN:

68004

Other (OTH)

AF:

0.0402

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

299

598

897

1196

1495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0504

Hom.:

Bravo

AF:

0.0381

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.0

(source)

DANN

Benign

0.76

PhyloP100

0.053

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over