chr6-116920446-A-G
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_173560.4(RFX6):āc.1319A>Gā(p.Tyr440Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
RFX6
NM_173560.4 missense
NM_173560.4 missense
Scores
6
5
8
Clinical Significance
Conservation
PhyloP100: 8.78
Genes affected
RFX6 (HGNC:21478): (regulatory factor X6) The nuclear protein encoded by this gene is a member of the regulatory factor X (RFX) family of transcription factors. Studies in mice suggest that this gene is specifically required for the differentiation of islet cells for the production of insulin, but not for the differentiation of pancreatic polypeptide-producing cells. It regulates the transcription factors involved in beta-cell maturation and function, thus, restricting the expression of the beta-cell differentiation and specification genes. Mutations in this gene are associated with Mitchell-Riley syndrome, which is characterized by neonatal diabetes with pancreatic hypoplasia, duodenal and jejunal atresia, and gall bladder agenesis.[provided by RefSeq, Sep 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.77
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RFX6 | NM_173560.4 | c.1319A>G | p.Tyr440Cys | missense_variant | 12/19 | ENST00000332958.3 | |
RFX6 | XM_011535589.2 | c.1211A>G | p.Tyr404Cys | missense_variant | 11/18 | ||
RFX6 | XM_017010477.2 | c.941A>G | p.Tyr314Cys | missense_variant | 11/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RFX6 | ENST00000332958.3 | c.1319A>G | p.Tyr440Cys | missense_variant | 12/19 | 1 | NM_173560.4 | P1 | |
RFX6 | ENST00000487683.5 | n.1383A>G | non_coding_transcript_exon_variant | 12/14 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460952Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 726898
GnomAD4 exome
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2
AN:
1460952
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30
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0
AN XY:
726898
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Monogenic diabetes Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Jul 07, 2016 | ACMG Criteria: PM2, PP3, BP4 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
D
Vest4
MutPred
Loss of catalytic residue at I439 (P = 0.0392);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at