Variant 3-186790139-T-TA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_002916.5(RFC4):c.996+2dupT variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000465 in 1,610,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 0 hom. )

Consequence

RFC4
NM_002916.5 splice_donor, intron

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.94

Variant links:

Genes affected

RFC4 (HGNC:9972): (replication factor C subunit 4) The elongation of primed DNA templates by DNA polymerase delta and DNA polymerase epsilon requires the accessory proteins proliferating cell nuclear antigen (PCNA) and replication factor C (RFC). RFC, also named activator 1, is a protein complex consisting of five distinct subunits of 140, 40, 38, 37, and 36 kD. This gene encodes the 37 kD subunit. This subunit forms a core complex with the 36 and 40 kDa subunits. The core complex possesses DNA-dependent ATPase activity, which was found to be stimulated by PCNA in an in vitro system. Alternatively spliced transcript variants encoding the same protein have been reported. [provided by RefSeq, Jul 2008]

RFC4 links:

RFC4 (HGNC:):

RFC4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.103479855 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.2, offset of 5, new splice context is: taaGTaggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-186790139-T-TA is Pathogenic according to our data. Variant chr3-186790139-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 3376522.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFC4	NM_002916.5 linkuse as main transcript	c.996+2dupT		splice_donor_variant, intron_variant		ENST00000296273.7	NP_002907.1	P35249-1
RFC4	NM_181573.3 linkuse as main transcript	c.996+2dupT		splice_donor_variant, intron_variant			NP_853551.1	P35249-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFC4	ENST00000296273.7 linkuse as main transcript	c.996+2dupT		splice_donor_variant, intron_variant		1	NM_002916.5	ENSP00000296273.2		P35249-1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000255

AC:

AN:

250968

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000985

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000475

AC:

693

AN:

1457752

Hom.:

Cov.:

AF XY:

0.000491

AC XY:

356

AN XY:

725406

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000537

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000581

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000580

Gnomad4 OTH exome

AF:

0.000332

GnomAD4 genome

AF:

0.000361

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000412

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

MORIMOTO-RYU-MALICDAN NEUROMUSCULAR SYNDROME

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.71

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over