9-3257130-T-A

Position:

• chr9-3257130-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001282116.2(RFX3):​c.1675A>T​(p.Thr559Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RFX3 NM_001282116.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RFX3. . Gene score misZ 3.4728 (greater than the threshold 3.09). Trascript score misZ 3.1742 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, autism spectrum disorder.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFX3	NM_001282116.2	c.1675A>T	p.Thr559Ser	missense_variant	14/17	ENST00000617270.5	NP_001269045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFX3	ENST00000617270.5	c.1675A>T	p.Thr559Ser	missense_variant	14/17	2	NM_001282116.2	ENSP00000482598	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 2022

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;D;.;.;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	.;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.53	D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.4	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D;.;D;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.016	D;.;D;D;T
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.41	B;B;P;.;.
Vest4		0.74
MutPred		0.26		Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);Gain of disorder (P = 0.0544);.;.;
MVP		0.52
MPC		2.1
ClinPred		0.96	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr9-3257130;