Genetic Variant RFC1:c.2954+34C>T (chr4-39295580-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.2954+34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,542,264 control chromosomes in the GnomAD database, including 30,292 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 0.17 ( 2461 hom., cov: 32)

Exomes 𝑓: 0.20 ( 27831 hom. )

Consequence

RFC1
NM_002913.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.383

Publications

21 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 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	Effect	Exon Rank	Protein	UniProt
RFC1	NM_002913.5	MANE Select	c.2954+34C>T	intron	N/A	NP_002904.3
RFC1	NM_001204747.2		c.2957+34C>T	intron	N/A	NP_001191676.1	P35251-1
RFC1	NM_001363496.2		c.2879+34C>T	intron	N/A	NP_001350425.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RFC1	ENST00000349703.7	TSL:1 MANE Select	c.2954+34C>T	intron	N/A	ENSP00000261424.4	P35251-2
RFC1	ENST00000381897.5	TSL:1	c.2957+34C>T	intron	N/A	ENSP00000371321.1	P35251-1
RFC1	ENST00000906184.1		c.2957+34C>T	intron	N/A	ENSP00000576243.1

Frequencies

GnomAD3 genomes

AF:

0.174

AC:

26331

AN:

151750

Hom.:

2460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.149

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.183

Gnomad EAS

AF:

0.0664

Gnomad SAS

AF:

0.197

Gnomad FIN

AF:

0.251

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.167

GnomAD2 exomes

AF:

0.183

AC:

40399

AN:

220356

AF XY:

0.189

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.130

Gnomad ASJ exome

AF:

0.180

Gnomad EAS exome

AF:

0.0610

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.176

GnomAD4 exome

AF:

0.196

AC:

272166

AN:

1390396

Hom.:

27831

Cov.:

AF XY:

0.197

AC XY:

135438

AN XY:

687164

show subpopulations

African (AFR)

AF:

0.118

AC:

3706

AN:

31414

American (AMR)

AF:

0.130

AC:

4820

AN:

37050

Ashkenazi Jewish (ASJ)

AF:

0.177

AC:

4231

AN:

23858

East Asian (EAS)

AF:

0.0665

AC:

2525

AN:

37978

South Asian (SAS)

AF:

0.219

AC:

16714

AN:

76192

European-Finnish (FIN)

AF:

0.235

AC:

12217

AN:

51998

Middle Eastern (MID)

AF:

0.184

AC:

1011

AN:

5504

European-Non Finnish (NFE)

AF:

0.202

AC:

216064

AN:

1069098

Other (OTH)

AF:

0.190

AC:

10878

AN:

57304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

9372

18744

28115

37487

46859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7548

15096

22644

30192

37740

<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:

0.173

AC:

26331

AN:

151868

Hom.:

2461

Cov.:

AF XY:

0.175

AC XY:

12954

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.119

AC:

4924

AN:

41418

American (AMR)

AF:

0.150

AC:

2287

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.183

AC:

636

AN:

3468

East Asian (EAS)

AF:

0.0664

AC:

343

AN:

5166

South Asian (SAS)

AF:

0.197

AC:

949

AN:

4814

European-Finnish (FIN)

AF:

0.251

AC:

2641

AN:

10506

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.207

AC:

14030

AN:

67924

Other (OTH)

AF:

0.165

AC:

347

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1093

2186

3280

4373

5466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

290

580

870

1160

1450

<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:

0.188

Hom.:

5738

Bravo

AF:

0.162

Asia WGS

AF:

0.135

AC:

470

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.066

(source)

DANN

Benign

0.79

PhyloP100

-0.38

Mutation Taster

=100/0

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

Computational scores

Splicing

Publications

Other links and lift over