Genetic Variant NM_002913.5:c.2860C>A (chr4-39295708-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002913.5(RFC1):c.2860C>A(p.Gln954Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,613,698 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 16 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 20 hom. )

Consequence

RFC1
NM_002913.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.00

Publications

4 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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008017927).

BP6

Variant 4-39295708-G-T is Benign according to our data. Variant chr4-39295708-G-T is described in ClinVar as Benign. ClinVar VariationId is 734652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00825 (1256/152228) while in subpopulation AFR AF = 0.0283 (1174/41520). AF 95% confidence interval is 0.0269. There are 16 homozygotes in GnomAd4. There are 601 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

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	UniProt
RFC1	NM_002913.5	MANE Select	c.2860C>A	p.Gln954Lys	missense	Exon 22 of 25	NP_002904.3
RFC1	NM_001204747.2		c.2863C>A	p.Gln955Lys	missense	Exon 22 of 25	NP_001191676.1	P35251-1
RFC1	NM_001363496.2		c.2785C>A	p.Gln929Lys	missense	Exon 21 of 24	NP_001350425.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFC1	ENST00000349703.7	TSL:1 MANE Select	c.2860C>A	p.Gln954Lys	missense	Exon 22 of 25	ENSP00000261424.4	P35251-2
RFC1	ENST00000381897.5	TSL:1	c.2863C>A	p.Gln955Lys	missense	Exon 22 of 25	ENSP00000371321.1	P35251-1
RFC1	ENST00000906184.1		c.2863C>A	p.Gln955Lys	missense	Exon 22 of 25	ENSP00000576243.1

Frequencies

GnomAD3 genomes

AF:

0.00823

AC:

1252

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0282

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00433

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00228

AC:

571

AN:

250986

AF XY:

0.00156

show subpopulations

Gnomad AFR exome

AF:

0.0312

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000818

AC:

1196

AN:

1461470

Hom.:

Cov.:

AF XY:

0.000706

AC XY:

513

AN XY:

727034

show subpopulations

African (AFR)

AF:

0.0298

AC:

996

AN:

33474

American (AMR)

AF:

0.00179

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111744

Other (OTH)

AF:

0.00167

AC:

101

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

107

160

214

267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00825

AC:

1256

AN:

152228

Hom.:

Cov.:

AF XY:

0.00808

AC XY:

601

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0283

AC:

1174

AN:

41520

American (AMR)

AF:

0.00432

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68026

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

112

167

223

279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00286

Hom.:

Bravo

AF:

0.00998

ESP6500AA

AF:

0.0293

AC:

129

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00273

AC:

332

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000547

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

RFC1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.094

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.4

PhyloP100

8.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

REVEL

Benign

0.18

Sift

Benign

0.16

Sift4G

Benign

0.43

Polyphen

0.98

Vest4

0.57

MVP

0.52

MPC

0.35

ClinPred

0.041

GERP RS

5.7

Varity_R

0.31

gMVP

0.61

Mutation Taster

=85/15

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

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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

Computational scores

Splicing

Publications

Other links and lift over