rs751954291

Variant names:

• chr19-5994855-G-A
• rs751954291
• NM_000635.4:c.2152C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000635.4(RFX2):​c.2152C>T​(p.His718Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000213 in 1,457,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H718R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: RFX2 NM_000635.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.56
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12273151).
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000635.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX2	NM_000635.4	MANE Select	c.2152C>T	p.His718Tyr	missense	Exon 18 of 18	NP_000626.2
	RFX2	NM_134433.3		c.2077C>T	p.His693Tyr	missense	Exon 17 of 17	NP_602309.1	P48378-2
	RANBP3-DT	NR_046376.1		n.112+16341G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX2	ENST00000303657.10	TSL:1 MANE Select	c.2152C>T	p.His718Tyr	missense	Exon 18 of 18	ENSP00000306335.4	P48378-1
	RFX2	ENST00000359161.7	TSL:1	c.2152C>T	p.His718Tyr	missense	Exon 18 of 18	ENSP00000352076.3	P48378-1
	RFX2	ENST00000926861.1		c.2173C>T	p.His725Tyr	missense	Exon 18 of 18	ENSP00000596920.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 246584 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1457644 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 725484

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.0000895 AC: 4 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111460

Other (OTH) AF: 0.0000166 AC: 1 AN: 60330

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T
Eigen	Benign	0.012
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.6
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.17	T
Polyphen		0.072	B
Vest4		0.10
MutPred		0.15		Gain of phosphorylation at H718 (P = 0.0042)
MVP		0.29
MPC		0.93
ClinPred		0.57	D
GERP RS		4.9
Varity_R		0.17
gMVP		0.51
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs751954291; hg19: chr19-5994866;