9-3225104-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/21 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

4
15

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.84
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 151 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RFX3NM_001282116.2 linkc.2188G>A p.Val730Ile missense_variant Exon 17 of 17 ENST00000617270.5 NP_001269045.1 P48380-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RFX3ENST00000617270.5 linkc.2188G>A p.Val730Ile missense_variant Exon 17 of 17 2 NM_001282116.2 ENSP00000482598.1 P48380-1
RFX3ENST00000382004.7 linkc.2188G>A p.Val730Ile missense_variant Exon 18 of 18 1 ENSP00000371434.3 P48380-1

Frequencies

GnomAD3 genomes
AF:
0.000992
AC:
151
AN:
152182
Hom.:
1
Cov.:
33
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
GnomAD3 exomes
AF:
0.00120
AC:
300
AN:
250858
Hom.:
1
AF XY:
0.00119
AC XY:
162
AN XY:
135588
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 SAS 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.:
3
Cov.:
31
AF XY:
0.00170
AC XY:
1236
AN XY:
727130
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00521
Gnomad4 NFE exome
AF:
0.00203
Gnomad4 OTH exome
AF:
0.000944
GnomAD4 genome
AF:
0.000991
AC:
151
AN:
152300
Hom.:
1
Cov.:
33
AF XY:
0.00110
AC XY:
82
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000313
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00443
Gnomad4 NFE
AF:
0.00129
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.00138
Hom.:
0
Bravo
AF:
0.000790
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00244
AC:
21
ExAC
AF:
0.00103
AC:
125
EpiCase
AF:
0.00120
EpiControl
AF:
0.000652

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

RFX3-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 08, 2024This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T;T
Eigen
Benign
0.027
Eigen_PC
Benign
0.21
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.92
.;D
M_CAP
Benign
0.0058
T
MetaRNN
Benign
0.0052
T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Benign
0.41
N;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.020
N;.
REVEL
Benign
0.061
Sift
Benign
0.039
D;.
Sift4G
Benign
0.98
T;T
Polyphen
0.13
B;B
Vest4
0.086
MVP
0.12
MPC
0.15
ClinPred
0.030
T
GERP RS
5.7
Varity_R
0.057
gMVP
0.056

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137899630; hg19: chr9-3225104; COSMIC: COSV65864777; API