ENST00000523629.6:c.1315G>A

Variant names:

• chr8-91975938-C-T
• ENST00000523629.6:c.1315G>A

Variant summary

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

The ENST00000523629.6(RUNX1T1):​c.1315G>A​(p.Gly439Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX1T1 ENST00000523629.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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]

ENSG00000253576 (HGNC:):

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, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1T1	NM_001198679.3	c.1492G>A	p.Gly498Arg	missense_variant	Exon 10 of 12		NP_001185608.1
RUNX1T1	NM_001395209.1	c.1399G>A	p.Gly467Arg	missense_variant	Exon 10 of 12		NP_001382138.1
RUNX1T1	NM_001198634.2	c.1348G>A	p.Gly450Arg	missense_variant	Exon 9 of 11		NP_001185563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1T1	ENST00000523629.6	c.1315G>A	p.Gly439Arg	missense_variant	Exon 10 of 12	5		ENSP00000428543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

RUNX1-IT1 related disorder Uncertain:1

-

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) • De novo variant with confirmed parentage in a patient with ear tags, dysmorphic features, global developmental delay, autism spectrum disorder, sleep concerns, behavior problems, and history of tremor referred for genetic testing at GeneDx -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	.;D;D;.;D;D;.;D;.;.;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;.;D;.;D;D;.;.;.;D;D;.
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.8	.;L;L;.;L;L;.;L;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.0	.;.;.;.;.;D;.;D;D;D;D;.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	.;.;.;.;.;D;.;D;D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.91	P;D;D;.;D;D;.;D;P;.;.;.;P
Vest4		0.85
MutPred		0.55		.;Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);.;Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);.;Gain of solvent accessibility (P = 0.0037);.;.;.;.;.;
MVP		0.62
MPC		1.7
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.71
gMVP		0.89

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: chr8-92988166;