NM_001282116.2:c.2173C>T

Variant names:

• chr9-3225119-G-A
• NM_001282116.2:c.2173C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001282116.2(RFX3):​c.2173C>T​(p.His725Tyr) 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 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: 7.89

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20837367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX3	NM_001282116.2	c.2173C>T	p.His725Tyr	missense_variant	Exon 17 of 17	ENST00000617270.5	NP_001269045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX3	ENST00000617270.5	c.2173C>T	p.His725Tyr	missense_variant	Exon 17 of 17	2	NM_001282116.2	ENSP00000482598.1
RFX3	ENST00000382004.7	c.2173C>T	p.His725Tyr	missense_variant	Exon 18 of 18	1		ENSP00000371434.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2173C>T (p.H725Y) alteration is located in exon 18 (coding exon 16) of the RFX3 gene. This alteration results from a C to T substitution at nucleotide position 2173, causing the histidine (H) at amino acid position 725 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.81	N;.
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.038	D;D
Polyphen		0.85	P;P
Vest4		0.40
MutPred		0.38		Gain of catalytic residue at I724 (P = 0.0416);Gain of catalytic residue at I724 (P = 0.0416);
MVP		0.26
MPC		0.30
ClinPred		0.89	D
GERP RS		5.7
Varity_R		0.38
gMVP		0.23

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-3225119; COSMIC: COSV101138146;