19-13962719-G-T

Variant names:

• chr19-13962719-G-T
• rs1048495559
• NM_002918.5:c.2916C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002918.5(RFX1):​c.2916C>A​(p.Phe972Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,529,428 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: RFX1 NM_002918.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0500
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21275938).
• BS2: High AC in GnomAdExome4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX1	NM_002918.5	c.2916C>A	p.Phe972Leu	missense_variant	Exon 21 of 21	ENST00000254325.9	NP_002909.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX1	ENST00000254325.9	c.2916C>A	p.Phe972Leu	missense_variant	Exon 21 of 21	1	NM_002918.5	ENSP00000254325.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000160 AC: 2 AN: 124920 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000434

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000269 AC: 37 AN: 1377322 Hom.: 0 Cov.: 35 AF XY: 0.0000250 AC XY: 17 AN XY: 679322

African (AFR) AF: 0.00 AC: 0 AN: 31188

American (AMR) AF: 0.00 AC: 0 AN: 35308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24878

East Asian (EAS) AF: 0.00 AC: 0 AN: 35456

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4762

European-Non Finnish (NFE) AF: 0.0000335 AC: 36 AN: 1076000

Other (OTH) AF: 0.00 AC: 0 AN: 57504

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2916C>A (p.F972L) alteration is located in exon 21 (coding exon 20) of the RFX1 gene. This alteration results from a C to A substitution at nucleotide position 2916, causing the phenylalanine (F) at amino acid position 972 to be replaced by a leucine (L). 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	0.85
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.050
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.047	D
Polyphen		0.15	B
Vest4		0.37
MutPred		0.20		Gain of helix (P = 0.062);
MVP		0.20
MPC		1.8
ClinPred		0.29	T
GERP RS		0.26
Varity_R		0.39
gMVP		0.50
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1048495559; hg19: chr19-14073531;