Genetic Variant RFX1:p.Ala975Thr (chr19-13962712-C-T) – 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.2923G>A(p.Ala975Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RFX1
NM_002918.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.20

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=0.18572932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX1	NM_002918.5 link	c.2923G>A	p.Ala975Thr	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.2923G>A	p.Ala975Thr	missense_variant	Exon 21 of 21	1	NM_002918.5	ENSP00000254325.3		P22670

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1376336

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678816

African (AFR)

AF:

0.00

AC:

AN:

31116

American (AMR)

AF:

0.00

AC:

AN:

35280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24854

East Asian (EAS)

AF:

0.00

AC:

AN:

35428

South Asian (SAS)

AF:

0.00

AC:

AN:

78636

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4386

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075782

Other (OTH)

AF:

0.00

AC:

AN:

57428

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2923G>A (p.A975T) alteration is located in exon 21 (coding exon 20) of the RFX1 gene. This alteration results from a G to A substitution at nucleotide position 2923, causing the alanine (A) at amino acid position 975 to be replaced by a threonine (T). 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

0.15

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.098

Eigen

Benign

-0.10

Eigen_PC

Benign

0.078

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.69

PhyloP100

1.2

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.31

REVEL

Benign

0.099

Sift

Uncertain

0.0030

Sift4G

Benign

0.15

Polyphen

0.075

Vest4

0.18

MutPred

0.21

Gain of sheet (P = 0.0477);

MVP

0.17

MPC

1.3

ClinPred

0.78

GERP RS

4.8

Varity_R

0.27

gMVP

0.26

Mutation Taster

=93/7

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