NM_000635.4:c.2105G>A

Variant names:

• chr19-5994902-C-T
• rs141415407
• NM_000635.4:c.2105G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000635.4(RFX2):​c.2105G>A​(p.Arg702His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000645 in 1,609,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: RFX2 NM_000635.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.139
• Publications: 0 publications found

Genes affected

RFX2 (HGNC:9983): (regulatory factor X2) This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly-conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X1, X3, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with other RFX family members. This protein can bind to cis elements in the promoter of the IL-5 receptor alpha gene. Two transcript variants encoding different isoforms have been described for this gene, and both variants utilize alternative polyadenylation sites. [provided by RefSeq, Jul 2008]

RANBP3-DT (HGNC:55312): (RANBP3 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02655372).
• BP6: Variant 19-5994902-C-T is Benign according to our data. Variant chr19-5994902-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2261960.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 68 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000635.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX2	NM_000635.4	MANE Select	c.2105G>A	p.Arg702His	missense	Exon 18 of 18	NP_000626.2
	RFX2	NM_134433.3		c.2030G>A	p.Arg677His	missense	Exon 17 of 17	NP_602309.1	P48378-2
	RANBP3-DT	NR_046376.1		n.112+16388C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX2	ENST00000303657.10	TSL:1 MANE Select	c.2105G>A	p.Arg702His	missense	Exon 18 of 18	ENSP00000306335.4	P48378-1
	RFX2	ENST00000359161.7	TSL:1	c.2105G>A	p.Arg702His	missense	Exon 18 of 18	ENSP00000352076.3	P48378-1
	RFX2	ENST00000926861.1		c.2126G>A	p.Arg709His	missense	Exon 18 of 18	ENSP00000596920.1

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000319 AC: 78 AN: 244210 AF XY: 0.000293

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000548

Gnomad NFE exome AF: 0.000534

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000666 AC: 971 AN: 1457606 Hom.: 1 Cov.: 31 AF XY: 0.000656 AC XY: 476 AN XY: 725462

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.000268 AC: 12 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86238

European-Finnish (FIN) AF: 0.0000607 AC: 3 AN: 49412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000820 AC: 912 AN: 1111860

Other (OTH) AF: 0.000431 AC: 26 AN: 60350

GnomAD4 genome AF: 0.000446 AC: 68 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74484

African (AFR) AF: 0.0000481 AC: 2 AN: 41586

American (AMR) AF: 0.000784 AC: 12 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000822 Hom.: 1

Bravo AF: 0.000465

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000297 AC: 36

EpiCase AF: 0.000763

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	1.8
DANN	Benign	0.94
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.14
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.16
Sift	Benign	0.20	T
Sift4G	Benign	0.13	T
Polyphen		0.0020	B
Vest4		0.11
MVP		0.22
MPC		0.99
ClinPred		0.025	T
GERP RS		-6.1
Varity_R		0.026
gMVP		0.19
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs141415407; hg19: chr19-5994913;