Genetic Variant RFC1:p.Pro847Pro (chr4-39300409-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002913.5(RFC1):c.2541A>G(p.Pro847Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,611,612 control chromosomes in the GnomAD database, including 253,413 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 18661 hom., cov: 32)

Exomes 𝑓: 0.56 ( 234752 hom. )

Consequence

RFC1
NM_002913.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.95

Publications

28 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 4-39300409-T-C is Benign according to our data. Variant chr4-39300409-T-C is described in ClinVar as Benign. ClinVar VariationId is 1327949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.95 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.617 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RFC1	NM_002913.5	MANE Select	c.2541A>G	p.Pro847Pro	synonymous	Exon 20 of 25	NP_002904.3
RFC1	NM_001204747.2		c.2544A>G	p.Pro848Pro	synonymous	Exon 20 of 25	NP_001191676.1
RFC1	NM_001363496.2		c.2466A>G	p.Pro822Pro	synonymous	Exon 19 of 24	NP_001350425.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RFC1	ENST00000349703.7	TSL:1 MANE Select	c.2541A>G	p.Pro847Pro	synonymous	Exon 20 of 25	ENSP00000261424.4
RFC1	ENST00000381897.5	TSL:1	c.2544A>G	p.Pro848Pro	synonymous	Exon 20 of 25	ENSP00000371321.1
RFC1	ENST00000505077.1	TSL:4	n.473A>G		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes

AF:

0.454

AC:

68910

AN:

151892

Hom.:

18663

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.541

Gnomad AMR

AF:

0.583

Gnomad ASJ

AF:

0.529

Gnomad EAS

AF:

0.636

Gnomad SAS

AF:

0.615

Gnomad FIN

AF:

0.545

Gnomad MID

AF:

0.563

Gnomad NFE

AF:

0.570

Gnomad OTH

AF:

0.484

GnomAD2 exomes

AF:

0.558

AC:

140006

AN:

250688

AF XY:

0.565

show subpopulations

Gnomad AFR exome

AF:

0.128

Gnomad AMR exome

AF:

0.660

Gnomad ASJ exome

AF:

0.532

Gnomad EAS exome

AF:

0.655

Gnomad FIN exome

AF:

0.548

Gnomad NFE exome

AF:

0.568

Gnomad OTH exome

AF:

0.564

GnomAD4 exome

AF:

0.562

AC:

819854

AN:

1459602

Hom.:

234752

Cov.:

AF XY:

0.564

AC XY:

409464

AN XY:

726176

show subpopulations

African (AFR)

AF:

0.123

AC:

4117

AN:

33396

American (AMR)

AF:

0.645

AC:

28810

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

0.539

AC:

14077

AN:

26120

East Asian (EAS)

AF:

0.644

AC:

25549

AN:

39690

South Asian (SAS)

AF:

0.593

AC:

51121

AN:

86164

European-Finnish (FIN)

AF:

0.554

AC:

29571

AN:

53408

Middle Eastern (MID)

AF:

0.521

AC:

2994

AN:

5746

European-Non Finnish (NFE)

AF:

0.568

AC:

631004

AN:

1110106

Other (OTH)

AF:

0.541

AC:

32611

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

16511

33021

49532

66042

82553

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17388

34776

52164

69552

86940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.453

AC:

68904

AN:

152010

Hom.:

18661

Cov.:

AF XY:

0.459

AC XY:

34083

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.139

AC:

5768

AN:

41468

American (AMR)

AF:

0.583

AC:

8909

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.529

AC:

1835

AN:

3470

East Asian (EAS)

AF:

0.635

AC:

3283

AN:

5170

South Asian (SAS)

AF:

0.615

AC:

2951

AN:

4800

European-Finnish (FIN)

AF:

0.545

AC:

5751

AN:

10560

Middle Eastern (MID)

AF:

0.551

AC:

162

AN:

294

European-Non Finnish (NFE)

AF:

0.570

AC:

38735

AN:

67954

Other (OTH)

AF:

0.483

AC:

1018

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1618

3237

4855

6474

8092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

628

1256

1884

2512

3140

<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:

0.526

Hom.:

34005

Bravo

AF:

0.441

Asia WGS

AF:

0.577

AC:

2009

AN:

3478

EpiCase

AF:

0.570

EpiControl

AF:

0.571

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

RFC1-related disorder

Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome

Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.5

(source)

DANN

Benign

0.59

PhyloP100

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over