Genetic Variant NM_005187.6:c.1378G>A (chr16-88881315-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005187.6(CBFA2T3):c.1378G>A(p.Ala460Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 1,589,462 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A460P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00054 ( 2 hom. )

Consequence

CBFA2T3
NM_005187.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.08

Publications

3 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:

ENSG00000259881 (HGNC:):

ENSG00000259881 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007025808).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005187.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBFA2T3	NM_005187.6	MANE Select	c.1378G>A	p.Ala460Thr	missense	Exon 9 of 12	NP_005178.4
	CBFA2T3	NM_175931.3		c.1120G>A	p.Ala374Thr	missense	Exon 8 of 11	NP_787127.1	O75081-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBFA2T3	ENST00000268679.9	TSL:1 MANE Select	c.1378G>A	p.Ala460Thr	missense	Exon 9 of 12	ENSP00000268679.4	O75081-1
CBFA2T3	ENST00000327483.9	TSL:1	c.1120G>A	p.Ala374Thr	missense	Exon 8 of 11	ENSP00000332122.5	O75081-2
CBFA2T3	ENST00000569464.5	TSL:1	c.1195G>A	p.Ala399Thr	missense	Exon 9 of 10	ENSP00000454851.1	H3BNH2

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000402

AC:

AN:

216506

AF XY:

0.000419

show subpopulations

Gnomad AFR exome

AF:

0.000302

Gnomad AMR exome

AF:

0.000247

Gnomad ASJ exome

AF:

0.000223

Gnomad EAS exome

AF:

0.0000592

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.000368

GnomAD4 exome

AF:

0.000540

AC:

776

AN:

1437164

Hom.:

Cov.:

AF XY:

0.000584

AC XY:

416

AN XY:

712848

show subpopulations

African (AFR)

AF:

0.000303

AC:

AN:

33032

American (AMR)

AF:

0.000209

AC:

AN:

43096

Ashkenazi Jewish (ASJ)

AF:

0.000236

AC:

AN:

25424

East Asian (EAS)

AF:

0.000128

AC:

AN:

39040

South Asian (SAS)

AF:

0.000985

AC:

AN:

84232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46392

Middle Eastern (MID)

AF:

0.00666

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.000526

AC:

579

AN:

1100962

Other (OTH)

AF:

0.000776

AC:

AN:

59282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.000223

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41568

American (AMR)

AF:

0.000261

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000239

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000233

AC:

ESP6500EA

AF:

0.000353

AC:

ExAC

AF:

0.000371

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.63

CADD

Benign

2.4

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.15

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.53

M_CAP

Benign

0.0037

MetaRNN

Benign

0.0070

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PhyloP100

-2.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.44

REVEL

Benign

0.010

Sift

Benign

0.64

Sift4G

Benign

0.51

Polyphen

0.0020

Vest4

0.058

MVP

0.11

MPC

0.062

ClinPred

0.0025

GERP RS

-2.9

Varity_R

0.030

gMVP

0.30

Mutation Taster

=93/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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