19-13963033-T-G

Position:

• chr19-13963033-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002918.5(RFX1):​c.2731A>C​(p.Asn911His) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RFX1 NM_002918.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.24

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3704096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFX1	NM_002918.5	c.2731A>C	p.Asn911His	missense_variant	20/21	ENST00000254325.9	NP_002909.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFX1	ENST00000254325.9	c.2731A>C	p.Asn911His	missense_variant	20/21	1	NM_002918.5	ENSP00000254325.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.2731A>C (p.N911H) alteration is located in exon 20 (coding exon 19) of the RFX1 gene. This alteration results from a A to C substitution at nucleotide position 2731, causing the asparagine (N) at amino acid position 911 to be replaced by a histidine (H). 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	0.11
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.69	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.042	D
Polyphen		0.99	D
Vest4		0.34
MutPred		0.19		Gain of helix (P = 0.0496);
MVP		0.24
MPC		0.95
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.29
gMVP		0.16

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: rs953834496; hg19: chr19-14073845;