Genetic Variant RFX4:c.44-4_44-3dupTT (chr12-106608780-C-CTT) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PVS1_ModerateBP6BS2

The NM_213594.3(RFX4):c.44-4_44-3dupTT variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00097 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RFX4
NM_213594.3 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.526

Variant links:

Genes affected

RFX4 (HGNC:9985): (regulatory factor X4) This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly-conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X1, X2, X3, and X5. It has been shown to interact with itself as well as with regulatory factors X2 and X3, but it does not interact with regulatory factor X1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2011]

RFX4 links:

ENSG00000257545 (HGNC:):

ENSG00000257545 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.039402176 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 0 (no position change), new splice context is: tcttttttttttttttttAGaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 12-106608780-C-CTT is Benign according to our data. Variant chr12-106608780-C-CTT is described in ClinVar as [Likely_benign]. Clinvar id is 3042661.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAdExome4 at 1231 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RFX4	NM_213594.3 link	c.44-4_44-3dupTT	splice_acceptor_variant, intron_variant	Intron 1 of 17	ENST00000392842.6	NP_998759.1	Q33E94-1
RFX4	NM_001206691.2 link	c.71-4_71-3dupTT	splice_acceptor_variant, intron_variant	Intron 1 of 17		NP_001193620.1	Q33E94-2
LOC100287944	NR_040246.1 link	n.143-100972_143-100971dupAA	intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX4	ENST00000392842.6 link	c.44-17_44-16insTT		intron_variant	Intron 1 of 17	1	NM_213594.3	ENSP00000376585.1		Q33E94-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

143726

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000966

AC:

1231

AN:

1274724

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

643

AN XY:

634904

show subpopulations

Gnomad4 AFR exome

AF:

0.000762

Gnomad4 AMR exome

AF:

0.00251

Gnomad4 ASJ exome

AF:

0.00140

Gnomad4 EAS exome

AF:

0.00170

Gnomad4 SAS exome

AF:

0.00272

Gnomad4 FIN exome

AF:

0.00118

Gnomad4 NFE exome

AF:

0.000759

Gnomad4 OTH exome

AF:

0.000960

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

143726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69746

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

RFX4-related disorder

Benign:1

Oct 19, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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