16-88877209-C-T

Variant names:

• chr16-88877209-C-T
• rs1023345928
• NM_005187.6:c.1729G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005187.6(CBFA2T3):​c.1729G>A​(p.Gly577Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000356 in 1,403,898 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CBFA2T3 NM_005187.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBFA2T3	NM_005187.6	c.1729G>A	p.Gly577Arg	missense_variant	Exon 12 of 12	ENST00000268679.9	NP_005178.4
CBFA2T3	NM_175931.3	c.1471G>A	p.Gly491Arg	missense_variant	Exon 11 of 11		NP_787127.1
CBFA2T3	XM_005256323.6	c.1654G>A	p.Gly552Arg	missense_variant	Exon 11 of 11		XP_005256380.1
CBFA2T3	XM_047434826.1	c.*1068G>A		3_prime_UTR_variant	Exon 11 of 11		XP_047290782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBFA2T3	ENST00000268679.9	c.1729G>A	p.Gly577Arg	missense_variant	Exon 12 of 12	1	NM_005187.6	ENSP00000268679.4
CBFA2T3	ENST00000327483.9	c.1471G>A	p.Gly491Arg	missense_variant	Exon 11 of 11	1		ENSP00000332122.5
CBFA2T3	ENST00000563856.1	n.696G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
CBFA2T3	ENST00000563920.1	n.834G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1403898 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 693180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000462

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1729G>A (p.G577R) alteration is located in exon 12 (coding exon 12) of the CBFA2T3 gene. This alteration results from a G to A substitution at nucleotide position 1729, causing the glycine (G) at amino acid position 577 to be replaced by an arginine (R). 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	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.60		.;Gain of MoRF binding (P = 0.0245);
MVP		0.60
MPC		1.9
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.84
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1023345928; hg19: chr16-88943617;