9-3248168-T-C

Variant names:

• chr9-3248168-T-C
• NM_001282116.2:c.1832A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001282116.2(RFX3):​c.1832A>G​(p.Asp611Gly) 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: 32)
• Consequence: RFX3 NM_001282116.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX3	NM_001282116.2	c.1832A>G	p.Asp611Gly	missense_variant	Exon 15 of 17	ENST00000617270.5	NP_001269045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX3	ENST00000617270.5	c.1832A>G	p.Asp611Gly	missense_variant	Exon 15 of 17	2	NM_001282116.2	ENSP00000482598.1
RFX3	ENST00000382004.7	c.1832A>G	p.Asp611Gly	missense_variant	Exon 16 of 18	1		ENSP00000371434.3
RFX3	ENST00000358730.6	c.1832A>G	p.Asp611Gly	missense_variant	Exon 14 of 14	1		ENSP00000351574.2
RFX3	ENST00000449234.1	c.227A>G	p.Asp76Gly	missense_variant	Exon 2 of 3	3		ENSP00000415594.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 02, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33658631) -

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	0.78	D;D;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.1	M;M;M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.0	D;.;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.035	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.97
MutPred		0.48		Loss of stability (P = 0.025);Loss of stability (P = 0.025);Loss of stability (P = 0.025);.;
MVP		0.80
MPC		2.6
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chr9-3248168;