dbSNP rs527683616: CBFA2T3:p.Glu612Gln (chr16-88877104-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_005187.6(CBFA2T3):c.1834G>C(p.Glu612Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. E612K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CBFA2T3
NM_005187.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.129

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]

CBFA2T3 links:

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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=0.075948834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBFA2T3	NM_005187.6 link	c.1834G>C	p.Glu612Gln	missense_variant	Exon 12 of 12	ENST00000268679.9	NP_005178.4	O75081-1
CBFA2T3	NM_175931.3 link	c.1576G>C	p.Glu526Gln	missense_variant	Exon 11 of 11		NP_787127.1	O75081-2
CBFA2T3	XM_005256323.6 link	c.1759G>C	p.Glu587Gln	missense_variant	Exon 11 of 11		XP_005256380.1
CBFA2T3	XM_047434826.1 link	c.*1173G>C		3_prime_UTR_variant	Exon 11 of 11		XP_047290782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CBFA2T3	ENST00000268679.9 link	c.1834G>C	p.Glu612Gln	missense_variant	Exon 12 of 12	1	NM_005187.6	ENSP00000268679.4	O75081-1
CBFA2T3	ENST00000327483.9 link	c.1576G>C	p.Glu526Gln	missense_variant	Exon 11 of 11	1		ENSP00000332122.5	O75081-2
CBFA2T3	ENST00000563856.1 link	n.801G>C		non_coding_transcript_exon_variant	Exon 3 of 3	2
CBFA2T3	ENST00000563920.1 link	n.939G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1392730

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686314

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:

AN:

31412

American (AMR)

AF:

0.00

AC:

AN:

35718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25072

East Asian (EAS)

AF:

0.00

AC:

AN:

35624

South Asian (SAS)

AF:

0.00

AC:

AN:

79066

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47044

Middle Eastern (MID)

AF:

0.000224

AC:

AN:

4462

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1076706

Other (OTH)

AF:

0.00

AC:

AN:

57626

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.068

.;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.076

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N

PhyloP100

-0.13

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.12

Sift

Benign

0.49

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.55

P;P

Vest4

0.052

MutPred

0.098

.;Loss of helix (P = 0.0558);

MVP

0.31

MPC

0.91

ClinPred

0.20

GERP RS

3.9

Varity_R

0.066

gMVP

0.24

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over