Genetic Variant RFC1:c.*908T>C (chr4-39287853-A-G) – 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.*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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.464

Publications

18 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=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFC1	NM_002913.5 link	c.*908T>C		3_prime_UTR_variant	Exon 25 of 25	ENST00000349703.7	NP_002904.3	P35251-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFC1	ENST00000349703.7 link	c.*908T>C		3_prime_UTR_variant	Exon 25 of 25	1	NM_002913.5	ENSP00000261424.4		P35251-2
RFC1	ENST00000381897.5 link	c.*908T>C		3_prime_UTR_variant	Exon 25 of 25	1		ENSP00000371321.1		P35251-1

Frequencies

GnomAD3 genomes

AF:

0.526

AC:

79929

AN:

151846

Hom.:

23205

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AF XY:

0.429

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

1.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.417

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.642

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.527

AC:

80030

AN:

151964

Hom.:

23245

Cov.:

AF XY:

0.521

AC XY:

38689

AN XY:

74264

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1719

3437

5156

6874

8593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

674

1348

2022

2696

3370

<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:

0.459

Hom.:

21503

Bravo

AF:

0.535

Asia WGS

AF:

0.430

AC:

1495

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

3.1

(source)

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)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over