19-6002836-C-G

Position:

• chr19-6002836-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000635.4(RFX2):​c.1535G>C​(p.Arg512Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RFX2 NM_000635.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

Genes affected

RFX2 (HGNC:9983): (regulatory factor X2) 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, X3, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with other RFX family members. This protein can bind to cis elements in the promoter of the IL-5 receptor alpha gene. Two transcript variants encoding different isoforms have been described for this gene, and both variants utilize alternative polyadenylation sites. [provided by RefSeq, Jul 2008]

RANBP3-DT (HGNC:55312): (RANBP3 divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFX2	NM_000635.4	c.1535G>C	p.Arg512Pro	missense_variant	14/18	ENST00000303657.10	NP_000626.2
RANBP3-DT	NR_046376.1	n.113-9284C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFX2	ENST00000303657.10	c.1535G>C	p.Arg512Pro	missense_variant	14/18	1	NM_000635.4	ENSP00000306335	P3
RANBP3-DT	ENST00000587836.1	n.113-9284C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.1535G>C (p.R512P) alteration is located in exon 14 (coding exon 13) of the RFX2 gene. This alteration results from a G to C substitution at nucleotide position 1535, causing the arginine (R) at amino acid position 512 to be replaced by a proline (P). 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	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Pathogenic	3.3	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.033	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.93
MutPred		0.60		Loss of MoRF binding (P = 7e-04);Loss of MoRF binding (P = 7e-04);.;
MVP		0.54
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.93
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-6002847;