chr9-3225113-C-G

Variant names:

• chr9-3225113-C-G
• rs1267719538
• NM_001282116.2:c.2179G>C

Variant summary

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

The NM_001282116.2(RFX3):​c.2179G>C​(p.Glu727Gln) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RFX3 NM_001282116.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.47
• Publications: 0 publications found

Genes affected

RFX3 (HGNC:9984): (regulatory factor X3) 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, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with other RFX family members. Multiple transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2013]

RFX3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen, Ambry Genetics
• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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=0.31908762).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282116.2. 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
	RFX3	NM_001282116.2	MANE Select	c.2179G>C	p.Glu727Gln	missense	Exon 17 of 17	NP_001269045.1	P48380-1
	RFX3	NM_001377999.1		c.2242G>C	p.Glu748Gln	missense	Exon 18 of 18	NP_001364928.1
	RFX3	NM_134428.3		c.2179G>C	p.Glu727Gln	missense	Exon 18 of 18	NP_602304.1	P48380-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX3	ENST00000617270.5	TSL:2 MANE Select	c.2179G>C	p.Glu727Gln	missense	Exon 17 of 17	ENSP00000482598.1	P48380-1
	RFX3	ENST00000382004.7	TSL:1	c.2179G>C	p.Glu727Gln	missense	Exon 18 of 18	ENSP00000371434.3	P48380-1
	RFX3	ENST00000968852.1		c.2242G>C	p.Glu748Gln	missense	Exon 18 of 18	ENSP00000638911.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.5
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.029	D
Polyphen		0.99	D
Vest4		0.43
MutPred		0.23		Loss of solvent accessibility (P = 0.0172)
MVP		0.37
MPC		0.65
ClinPred		0.79	D
GERP RS		5.7
Varity_R		0.35
gMVP		0.41
Mutation Taster		=60/40	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: rs1267719538; hg19: chr9-3225113;