chr4-39319011-T-C

Variant names:

• chr4-39319011-T-C
• rs11096991
• NM_002913.5:c.1095+1372A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002913.5(RFC1):​c.1095+1372A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 152,088 control chromosomes in the GnomAD database, including 8,424 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 0.33 (8424 hom., cov: 32)
• Consequence: RFC1 NM_002913.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.228
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFC1	NM_002913.5	c.1095+1372A>G		intron_variant	Intron 9 of 24	ENST00000349703.7	NP_002904.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFC1	ENST00000349703.7	c.1095+1372A>G		intron_variant	Intron 9 of 24	1	NM_002913.5	ENSP00000261424.4
RFC1	ENST00000381897.5	c.1095+1372A>G		intron_variant	Intron 9 of 24	1		ENSP00000371321.1
RFC1	ENST00000512881.5	n.497+1372A>G		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50096 AN: 151970 Hom.: 8420 Cov.: 32

Gnomad AFR AF: 0.308

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.316

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.329 AC: 50112 AN: 152088 Hom.: 8424 Cov.: 32 AF XY: 0.327 AC XY: 24273 AN XY: 74314

African (AFR) AF: 0.308 AC: 12779 AN: 41510

American (AMR) AF: 0.281 AC: 4293 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1253 AN: 3470

East Asian (EAS) AF: 0.181 AC: 938 AN: 5182

South Asian (SAS) AF: 0.308 AC: 1485 AN: 4822

European-Finnish (FIN) AF: 0.409 AC: 4309 AN: 10540

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23979 AN: 67968

Other (OTH) AF: 0.313 AC: 661 AN: 2114

Alfa AF: 0.345 Hom.: 1909

Bravo AF: 0.318

Asia WGS AF: 0.231 AC: 802 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.7
DANN	Benign	0.57
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11096991; hg19: chr4-39320631;