NM_000635.4:c.1808C>A

Variant names:

• chr19-6001866-G-T
• rs771131239
• NM_000635.4:c.1808C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000635.4(RFX2):​c.1808C>A​(p.Pro603His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P603L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RFX2 NM_000635.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.56
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39413178).

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.1808C>A	p.Pro603His	missense	Exon 15 of 18	NP_000626.2
	RFX2	NM_134433.3		c.1733C>A	p.Pro578His	missense	Exon 14 of 17	NP_602309.1	P48378-2
	RANBP3-DT	NR_046376.1		n.113-10254G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX2	ENST00000303657.10	TSL:1 MANE Select	c.1808C>A	p.Pro603His	missense	Exon 15 of 18	ENSP00000306335.4	P48378-1
	RFX2	ENST00000359161.7	TSL:1	c.1808C>A	p.Pro603His	missense	Exon 15 of 18	ENSP00000352076.3	P48378-1
	RFX2	ENST00000926861.1		c.1808C>A	p.Pro603His	missense	Exon 15 of 18	ENSP00000596920.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000193 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.44
MutPred		0.31		Loss of glycosylation at P603 (P = 0.0502)
MVP		0.27
MPC		1.9
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.66
gMVP		0.32
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs771131239; hg19: chr19-6001877; COSMIC: COSV100353707; COSMIC: COSV100353707;