8-91970747-C-T

Variant names:

• chr8-91970747-C-T
• rs1812656025
• ENST00000523629.6:c.1450G>A

Variant summary

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

The NM_001198679.3(RUNX1T1):​c.1627G>A​(p.Ala543Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RUNX1T1 NM_001198679.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

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.1627G>A	p.Ala543Thr	missense_variant	Exon 11 of 12		NP_001185608.1
RUNX1T1	NM_001395209.1	c.1534G>A	p.Ala512Thr	missense_variant	Exon 11 of 12		NP_001382138.1
RUNX1T1	NM_001198634.2	c.1483G>A	p.Ala495Thr	missense_variant	Exon 10 of 11		NP_001185563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1T1	ENST00000523629.6	c.1450G>A	p.Ala484Thr	missense_variant	Exon 11 of 12	5		ENSP00000428543.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 23, 2023

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 (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;D;D;.;D;D;.;D;.;.;.;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;.;.;D;.;D;D;.;.;.;D;D;.
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.5	.;L;L;.;L;L;.;L;.;.;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.2	.;.;.;D;.;N;.;N;N;N;N;D;N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	.;.;.;D;.;T;.;T;T;T;T;D;T
Sift4G	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.036	B;B;B;.;B;B;.;B;B;.;.;.;B
Vest4		0.74
MutPred		0.17		.;Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;Gain of helix (P = 0.0425);.;.;.;.;.;
MVP		0.31
MPC		0.71
ClinPred		0.59	D
GERP RS		5.8
Varity_R		0.27
gMVP		0.88

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: rs1812656025; hg19: chr8-92982975;