16-88881315-C-T

Variant names:

• chr16-88881315-C-T
• rs200535158
• NM_005187.6:c.1378G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 15/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.08

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]

ENSG00000259881 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007025808).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBFA2T3	NM_005187.6	c.1378G>A	p.Ala460Thr	missense_variant	Exon 9 of 12	ENST00000268679.9	NP_005178.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBFA2T3	ENST00000268679.9	c.1378G>A	p.Ala460Thr	missense_variant	Exon 9 of 12	1	NM_005187.6	ENSP00000268679.4

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152180 Hom.: 0 Cov.: 34

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

GnomAD3 exomes AF: 0.000402 AC: 87 AN: 216506 Hom.: 0 AF XY: 0.000419 AC XY: 50 AN XY: 119264

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 SAS exome AF: 0.00111

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.: 2 Cov.: 32 AF XY: 0.000584 AC XY: 416 AN XY: 712848

Gnomad4 AFR exome AF: 0.000303

Gnomad4 AMR exome AF: 0.000209

Gnomad4 ASJ exome AF: 0.000236

Gnomad4 EAS exome AF: 0.000128

Gnomad4 SAS exome AF: 0.000985

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000526

Gnomad4 OTH exome AF: 0.000776

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152298 Hom.: 0 Cov.: 34 AF XY: 0.000282 AC XY: 21 AN XY: 74480

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.000353 AC: 3

ExAC AF: 0.000371 AC: 44

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1378G>A (p.A460T) alteration is located in exon 9 (coding exon 9) of the CBFA2T3 gene. This alteration results from a G to A substitution at nucleotide position 1378, causing the alanine (A) at amino acid position 460 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.4
DANN	Benign	0.93
DEOGEN2	Benign	0.15	.;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	.;N;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.44	N;N;N
REVEL	Benign	0.010
Sift	Benign	0.64	T;T;T
Sift4G	Benign	0.51	T;T;.
Polyphen		0.0020	B;B;.
Vest4		0.058
MVP		0.11
MPC		0.062
ClinPred		0.0025	T
GERP RS		-2.9
Varity_R		0.030
gMVP		0.30

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

Other links and lift over

dbSNP: rs200535158; hg19: chr16-88947723;