Genetic Variant RFX1:p.Thr956Ile (chr19-13962768-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002918.5(RFX1):c.2867C>T(p.Thr956Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,378,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

RFX1
NM_002918.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17

Publications

0 publications found

Variant links:

Genes affected

RFX1 (HGNC:9982): (regulatory factor X1) This gene encodes a member of the regulatory factor X (RFX) family of transcription factors, which are characterized by a winged-helix DNA-binding domain. The encoded transcription factor contains an N-terminal activation domain and a C-terminal repression domain, and may activate or repress target gene expression depending on cellular context. This transcription factor has been shown to regulate a wide variety of genes involved in immunity and cancer, including the MHC class II genes and genes that may be involved in cancer progression. This gene exhibits altered expression in glioblastoma and the autoimmune disease systemic lupus erythematosis (SLE). [provided by RefSeq, Jul 2016]

RFX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.110533535).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX1	NM_002918.5 link	c.2867C>T	p.Thr956Ile	missense_variant	Exon 21 of 21	ENST00000254325.9	NP_002909.4	P22670

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX1	ENST00000254325.9 link	c.2867C>T	p.Thr956Ile	missense_variant	Exon 21 of 21	1	NM_002918.5	ENSP00000254325.3		P22670

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.25e-7

AC:

AN:

1378434

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

679782

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31292

American (AMR)

AF:

0.0000286

AC:

AN:

34990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24878

East Asian (EAS)

AF:

0.00

AC:

AN:

35552

South Asian (SAS)

AF:

0.00

AC:

AN:

78662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075706

Other (OTH)

AF:

0.00

AC:

AN:

57568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2867C>T (p.T956I) alteration is located in exon 21 (coding exon 20) of the RFX1 gene. This alteration results from a C to T substitution at nucleotide position 2867, causing the threonine (T) at amino acid position 956 to be replaced by an isoleucine (I). 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

0.12

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

3.2

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.89

REVEL

Benign

0.087

Sift

Benign

0.11

Sift4G

Uncertain

0.047

Polyphen

0.054

Vest4

0.047

MutPred

0.089

Loss of phosphorylation at T956 (P = 0.0143);

MVP

0.068

MPC

0.99

ClinPred

0.36

GERP RS

2.1

Varity_R

0.13

gMVP

0.21

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over