Genetic Variant RFX4:c.44-7448A>G (chr12-106601349-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001206691.2(RFX4):c.70+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,578,056 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 24 hom. )

Consequence

RFX4
NM_001206691.2 splice_region, intron

Scores

Splicing: ADA: 0.02036

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.45

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 12-106601349-A-G is Benign according to our data. Variant chr12-106601349-A-G is described in ClinVar as [Benign]. Clinvar id is 719284.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 539 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RFX4	NM_213594.3 link	c.44-7448A>G	intron_variant	Intron 1 of 17	ENST00000392842.6	NP_998759.1	Q33E94-1
RFX4	NM_001206691.2 link	c.70+3A>G	splice_region_variant, intron_variant	Intron 1 of 17		NP_001193620.1	Q33E94-2
LOC100287944	NR_040246.1 link	n.143-93539T>C	intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX4	ENST00000392842.6 link	c.44-7448A>G		intron_variant	Intron 1 of 17	1	NM_213594.3	ENSP00000376585.1		Q33E94-1

Frequencies

GnomAD3 genomes

AF:

0.00354

AC:

539

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00406

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00548

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00361

AC:

691

AN:

191440

Hom.:

AF XY:

0.00378

AC XY:

389

AN XY:

102826

show subpopulations

Gnomad AFR exome

AF:

0.000813

Gnomad AMR exome

AF:

0.00100

Gnomad ASJ exome

AF:

0.00965

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00237

Gnomad FIN exome

AF:

0.00252

Gnomad NFE exome

AF:

0.00553

Gnomad OTH exome

AF:

0.00474

GnomAD4 exome

AF:

0.00438

AC:

6247

AN:

1425734

Hom.:

Cov.:

AF XY:

0.00432

AC XY:

3054

AN XY:

706142

show subpopulations

Gnomad4 AFR exome

AF:

0.000738

Gnomad4 AMR exome

AF:

0.00187

Gnomad4 ASJ exome

AF:

0.0115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00192

Gnomad4 FIN exome

AF:

0.00306

Gnomad4 NFE exome

AF:

0.00482

Gnomad4 OTH exome

AF:

0.00440

GnomAD4 genome

AF:

0.00354

AC:

539

AN:

152322

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000649

Gnomad4 AMR

AF:

0.00405

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00548

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00549

Hom.:

Bravo

AF:

0.00409

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.020

dbscSNV1_RF

Benign

0.036

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

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