16-88881326-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005187.6(CBFA2T3):​c.1367G>C​(p.Arg456Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,433,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R456H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CBFA2T3
NM_005187.6 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.56

Publications

0 publications found
Variant links:
Genes affected
CBFA2T3 (HGNC:1537): (CBFA2/RUNX1 partner transcriptional co-repressor 3) This gene encodes a member of the myeloid translocation gene family which interact with DNA-bound transcription factors and recruit a range of corepressors to facilitate transcriptional repression. The t(16;21)(q24;q22) translocation is one of the less common karyotypic abnormalities in acute myeloid leukemia. The translocation produces a chimeric gene made up of the 5'-region of the runt-related transcription factor 1 gene fused to the 3'-region of this gene. This gene is also a putative breast tumor suppressor. Alternative splicing results in transcript variants. [provided by RefSeq, Nov 2010]

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1617986).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CBFA2T3NM_005187.6 linkc.1367G>C p.Arg456Pro missense_variant Exon 9 of 12 ENST00000268679.9 NP_005178.4 O75081-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CBFA2T3ENST00000268679.9 linkc.1367G>C p.Arg456Pro missense_variant Exon 9 of 12 1 NM_005187.6 ENSP00000268679.4 O75081-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
6.97e-7
AC:
1
AN:
1433840
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
710968
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32910
American (AMR)
AF:
0.00
AC:
0
AN:
42300
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25478
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38722
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84036
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
46234
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5716
European-Non Finnish (NFE)
AF:
9.10e-7
AC:
1
AN:
1099270
Other (OTH)
AF:
0.00
AC:
0
AN:
59174
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.325
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
16
DANN
Benign
0.95
DEOGEN2
Benign
0.14
.;T;T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.52
D
LIST_S2
Benign
0.72
T;T;T
M_CAP
Benign
0.050
D
MetaRNN
Benign
0.16
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
.;N;.
PhyloP100
1.6
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.4
N;N;N
REVEL
Benign
0.13
Sift
Benign
0.24
T;T;T
Sift4G
Benign
0.26
T;T;.
Polyphen
0.51
P;P;.
Vest4
0.15
MutPred
0.24
.;Gain of glycosylation at R456 (P = 0.0068);.;
MVP
0.48
MPC
0.13
ClinPred
0.25
T
GERP RS
2.6
Varity_R
0.28
gMVP
0.34

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

Other links and lift over

dbSNP: rs756757934; hg19: chr16-88947734; API