12-106687018-G-A

Variant names:

• chr12-106687018-G-A
• rs778949159
• NM_213594.3:c.512G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_213594.3(RFX4):​c.512G>A​(p.Arg171Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RFX4 NM_213594.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.56

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]

ENSG00000257545 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX4	NM_213594.3	c.512G>A	p.Arg171Gln	missense_variant	Exon 6 of 18	ENST00000392842.6	NP_998759.1
RFX4	NM_001206691.2	c.539G>A	p.Arg180Gln	missense_variant	Exon 6 of 18		NP_001193620.1
RFX4	NM_032491.6	c.230G>A	p.Arg77Gln	missense_variant	Exon 2 of 14		NP_115880.2
LOC100287944	NR_040246.1	n.142+87672C>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX4	ENST00000392842.6	c.512G>A	p.Arg171Gln	missense_variant	Exon 6 of 18	1	NM_213594.3	ENSP00000376585.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251480 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.0000165 AC XY: 12 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.539G>A (p.R180Q) alteration is located in exon 6 (coding exon 6) of the RFX4 gene. This alteration results from a G to A substitution at nucleotide position 539, causing the arginine (R) at amino acid position 180 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.057	T;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.34	N;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.86	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.51	T;T;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.74
MutPred		0.35		Gain of ubiquitination at K173 (P = 0.0417);.;.;.;
MVP		0.26
MPC		1.3
ClinPred		0.78	D
GERP RS		5.8
Varity_R		0.21
gMVP		0.84

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: rs778949159; hg19: chr12-107080796; COSMIC: COSV99986225; COSMIC: COSV99986225;