Genetic Variant RFX3:p.Val730Ile (chr9-3225104-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001282116.2(RFX3):c.2188G>A(p.Val730Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,613,946 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00099 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 3 hom. )

Consequence

RFX3
NM_001282116.2 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.84

Publications

8 publications found

Variant links:

Genes affected

RFX3 (HGNC:9984): (regulatory factor X3) 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, X2, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with other RFX family members. Multiple transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2013]

RFX3 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen, Ambry Genetics
autism spectrum disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

RFX3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005207628).

BP6

Variant 9-3225104-C-T is Benign according to our data. Variant chr9-3225104-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3042204.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000991 (151/152300) while in subpopulation NFE AF = 0.00129 (88/68030). AF 95% confidence interval is 0.00107. There are 1 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 151 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFX3	NM_001282116.2	MANE Select	c.2188G>A	p.Val730Ile	missense	Exon 17 of 17	NP_001269045.1	P48380-1
RFX3	NM_001377999.1		c.2251G>A	p.Val751Ile	missense	Exon 18 of 18	NP_001364928.1
RFX3	NM_134428.3		c.2188G>A	p.Val730Ile	missense	Exon 18 of 18	NP_602304.1	P48380-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RFX3	ENST00000617270.5	TSL:2 MANE Select	c.2188G>A	p.Val730Ile	missense	Exon 17 of 17	ENSP00000482598.1	P48380-1
RFX3	ENST00000382004.7	TSL:1	c.2188G>A	p.Val730Ile	missense	Exon 18 of 18	ENSP00000371434.3	P48380-1
RFX3	ENST00000968852.1		c.2251G>A	p.Val751Ile	missense	Exon 18 of 18	ENSP00000638911.1

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00443

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00120

AC:

300

AN:

250858

AF XY:

0.00119

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00504

Gnomad NFE exome

AF:

0.00161

Gnomad OTH exome

AF:

0.000820

GnomAD4 exome

AF:

0.00178

AC:

2596

AN:

1461646

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

1236

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00521

AC:

278

AN:

53394

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00203

AC:

2254

AN:

1111900

Other (OTH)

AF:

0.000944

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

153

306

459

612

765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

180

270

360

450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000991

AC:

151

AN:

152300

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41556

American (AMR)

AF:

0.000131

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00443

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00130

Hom.:

Bravo

AF:

0.000790

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00103

AC:

125

EpiCase

AF:

0.00120

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

RFX3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

Eigen

Benign

0.027

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0052

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.41

PhyloP100

2.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.020

REVEL

Benign

0.061

Sift

Benign

0.039

Sift4G

Benign

0.98

Polyphen

0.13

Vest4

0.086

MVP

0.12

MPC

0.15

ClinPred

0.030

GERP RS

5.7

Varity_R

0.057

gMVP

0.056

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over