12-106682011-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_213594.3(RFX4):​c.334C>T​(p.Pro112Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RFX4
NM_213594.3 missense

Scores

9
8
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.41
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RFX4NM_213594.3 linkc.334C>T p.Pro112Ser missense_variant Exon 5 of 18 ENST00000392842.6 NP_998759.1 Q33E94-1
RFX4NM_001206691.2 linkc.361C>T p.Pro121Ser missense_variant Exon 5 of 18 NP_001193620.1 Q33E94-2
LOC100505978NR_038912.1 linkn.443G>A non_coding_transcript_exon_variant Exon 3 of 4
LOC100287944NR_040246.1 linkn.142+92679G>A intron_variant Intron 1 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RFX4ENST00000392842.6 linkc.334C>T p.Pro112Ser missense_variant Exon 5 of 18 1 NM_213594.3 ENSP00000376585.1 Q33E94-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461872
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727238
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.361C>T (p.P121S) alteration is located in exon 5 (coding exon 5) of the RFX4 gene. This alteration results from a C to T substitution at nucleotide position 361, causing the proline (P) at amino acid position 121 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
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
D;.;.;.
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Uncertain
2.1
M;.;.;.
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-5.6
D;D;D;D
REVEL
Pathogenic
0.81
Sift
Benign
0.092
T;T;T;D
Sift4G
Uncertain
0.018
D;T;D;D
Polyphen
0.058
B;.;D;.
Vest4
0.85
MutPred
0.80
Gain of MoRF binding (P = 0.0506);.;.;.;
MVP
0.46
MPC
0.46
ClinPred
0.99
D
GERP RS
5.2
Varity_R
0.45
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.27
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.27
Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs867953455; hg19: chr12-107075789; COSMIC: COSV57575006; COSMIC: COSV57575006; API