12-106639364-C-T

Variant names:

• chr12-106639364-C-T
• rs2040573753
• NM_213594.3:c.163C>T

Variant summary

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

The NM_213594.3(RFX4):​c.163C>T​(p.Pro55Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFX4 NM_213594.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49

Genes affected

RFX4 (HGNC:9985): (regulatory factor X4) 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, X3, and X5. It has been shown to interact with itself as well as with regulatory factors X2 and X3, but it does not interact with regulatory factor X1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2011]

ENSG00000257545 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX4	NM_213594.3	c.163C>T	p.Pro55Ser	missense_variant	Exon 3 of 18	ENST00000392842.6	NP_998759.1
RFX4	NM_001206691.2	c.190C>T	p.Pro64Ser	missense_variant	Exon 3 of 18		NP_001193620.1
LOC100287944	NR_040246.1	n.143-131554G>A		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX4	ENST00000392842.6	c.163C>T	p.Pro55Ser	missense_variant	Exon 3 of 18	1	NM_213594.3	ENSP00000376585.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.190C>T (p.P64S) alteration is located in exon 3 (coding exon 3) of the RFX4 gene. This alteration results from a C to T substitution at nucleotide position 190, causing the proline (P) at amino acid position 64 to be replaced by a serine (S). 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	Uncertain	0.50
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.23
Sift	Benign	0.10	T;T
Sift4G	Benign	0.70	T;T
Polyphen		1.0	D;D
Vest4		0.70
MutPred		0.30		Loss of helix (P = 0.0376);.;
MVP		0.043
MPC		0.75
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.14
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs2040573753; hg19: chr12-107033142;