dbSNP rs1973805589: RFX1:p.Leu778Phe (chr19-13963887-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_002918.5(RFX1):c.2332C>T(p.Leu778Phe) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L778I) has been classified 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

Not reported in ClinVar

Conservation

PhyloP100: 9.93

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX1	NM_002918.5 link	c.2332C>T	p.Leu778Phe	missense_variant	Exon 17 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.2332C>T	p.Leu778Phe	missense_variant	Exon 17 of 21	1	NM_002918.5	ENSP00000254325.3		P22670
RFX1	ENST00000588520.1 link	n.169C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1396882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689604

African (AFR)

AF:

0.00

AC:

AN:

31502

American (AMR)

AF:

0.00

AC:

AN:

35910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25130

East Asian (EAS)

AF:

0.00

AC:

AN:

35702

South Asian (SAS)

AF:

0.00

AC:

AN:

79240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4198

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080324

Other (OTH)

AF:

0.00

AC:

AN:

57862

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PhyloP100

9.9

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.26

Sift

Benign

0.070

Sift4G

Uncertain

0.060

Polyphen

0.94

Vest4

0.81

MVP

0.21

MPC

2.1

ClinPred

0.99

GERP RS

3.8

Varity_R

0.44

gMVP

0.83

Mutation Taster

=45/55

disease causing

(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

Computational scores

Splicing

Publications

Other links and lift over