8-91960402-C-T

Variant names:

• chr8-91960402-C-T
• ENST00000523629.6:c.1655G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001198679.3(RUNX1T1):​c.1832G>A​(p.Gly611Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RUNX1T1 NM_001198679.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

RUNX1T1 (HGNC:1535): (RUNX1 partner transcriptional co-repressor 1) 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(8;21)(q22;q22) translocation is one of the most frequent 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. The chimeric protein is thought to associate with the nuclear corepressor/histone deacetylase complex to block hematopoietic differentiation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1T1	NM_001198679.3	c.1832G>A	p.Gly611Glu	missense_variant	Exon 12 of 12		NP_001185608.1
RUNX1T1	NM_001395209.1	c.1739G>A	p.Gly580Glu	missense_variant	Exon 12 of 12		NP_001382138.1
RUNX1T1	NM_001198634.2	c.1688G>A	p.Gly563Glu	missense_variant	Exon 11 of 11		NP_001185563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1T1	ENST00000523629.6	c.1655G>A	p.Gly552Glu	missense_variant	Exon 12 of 12	5		ENSP00000428543.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 02, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	.;D;D;.;D;D;.;D;.;.;.;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;.;.;D;.;D;D;.;.;.;D;D;.
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	.;L;L;.;L;L;.;L;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.3	.;.;.;.;.;D;.;D;D;D;D;.;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.012	.;.;.;.;.;D;.;D;D;D;D;.;D
Sift4G	Uncertain	0.023	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.096	B;P;P;.;P;P;.;P;B;.;.;.;B
Vest4		0.79
MutPred		0.38		.;Gain of catalytic residue at G552 (P = 0.0458);Gain of catalytic residue at G552 (P = 0.0458);.;Gain of catalytic residue at G552 (P = 0.0458);Gain of catalytic residue at G552 (P = 0.0458);.;Gain of catalytic residue at G552 (P = 0.0458);.;.;.;.;.;
MVP		0.61
MPC		1.5
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.55
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-92972630;