NM_005187.6:c.1367G>C

Variant names:

• chr16-88881326-C-G
• rs756757934
• NM_005187.6:c.1367G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

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

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).

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.1367G>C	p.Arg456Pro	missense	Exon 9 of 12	NP_005178.4
	CBFA2T3	NM_175931.3		c.1109G>C	p.Arg370Pro	missense	Exon 8 of 11	NP_787127.1	O75081-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBFA2T3	ENST00000268679.9	TSL:1 MANE Select	c.1367G>C	p.Arg456Pro	missense	Exon 9 of 12	ENSP00000268679.4	O75081-1
	CBFA2T3	ENST00000327483.9	TSL:1	c.1109G>C	p.Arg370Pro	missense	Exon 8 of 11	ENSP00000332122.5	O75081-2
	CBFA2T3	ENST00000569464.5	TSL:1	c.1184G>C	p.Arg395Pro	missense	Exon 9 of 10	ENSP00000454851.1	H3BNH2

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

⚠️ 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), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.13
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Polyphen		0.51	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

Other links and lift over

dbSNP: rs756757934; hg19: chr16-88947734;