4-39295708-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.00

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFC1	NM_002913.5	c.2860C>A	p.Gln954Lys	missense_variant	22/25	ENST00000349703.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFC1	ENST00000349703.7	c.2860C>A	p.Gln954Lys	missense_variant	22/25	1	NM_002913.5	P4
RFC1	ENST00000381897.5	c.2863C>A	p.Gln955Lys	missense_variant	22/25	1		A2
RFC1	ENST00000510783.5	n.75C>A		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.00823 AC: 1252 AN: 152110 Hom.: 16 Cov.: 32

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

GnomAD3 exomes AF: 0.00228 AC: 571 AN: 250986 Hom.: 13 AF XY: 0.00156 AC XY: 211 AN XY: 135644

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 SAS 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.: 20 Cov.: 31 AF XY: 0.000706 AC XY: 513 AN XY: 727034

Gnomad4 AFR exome AF: 0.0298

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.00167

GnomAD4 genome AF: 0.00825 AC: 1256 AN: 152228 Hom.: 16 Cov.: 32 AF XY: 0.00808 AC XY: 601 AN XY: 74422

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00161 Hom.: 10

Bravo AF: 0.00998

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00273 AC: 332

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RFC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2019

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0080	T;T
MetaSVM	Benign	-0.85	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.18
Sift	Benign	0.16	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.98	D;P
Vest4		0.57
MVP		0.52
MPC		0.35
ClinPred		0.041	T
GERP RS		5.7
Varity_R		0.31
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs17335452; hg19: chr4-39297328;