8-91960387-G-C

Variant names:

• chr8-91960387-G-C
• ENST00000523629.6:c.1670C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001198679.3(RUNX1T1):​c.1847C>G​(p.Ala616Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 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: 6.05

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12772349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1T1	NM_001198679.3	c.1847C>G	p.Ala616Gly	missense_variant	Exon 12 of 12		NP_001185608.1
RUNX1T1	NM_001395209.1	c.1754C>G	p.Ala585Gly	missense_variant	Exon 12 of 12		NP_001382138.1
RUNX1T1	NM_001198634.2	c.1703C>G	p.Ala568Gly	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.1670C>G	p.Ala557Gly	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 specified Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1847C>G (p.A616G) alteration is located in exon 12 (coding exon 12) of the RUNX1T1 gene. This alteration results from a C to G substitution at nucleotide position 1847, causing the alanine (A) at amino acid position 616 to be replaced by a glycine (G). 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	Benign	0.090
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.30	.;T;T;.;T;T;.;T;.;.;.;.;.
Eigen	Benign	-0.037
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;.;D;.;D;D;.;.;.;D;D;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.46	.;N;N;.;N;N;.;N;.;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.010	.;.;.;.;.;N;.;N;N;N;N;.;N
REVEL	Benign	0.17
Sift	Benign	0.67	.;.;.;.;.;T;.;T;T;T;T;.;T
Sift4G	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;.;B;B;.;B;B;.;.;.;B
Vest4		0.17
MutPred		0.21		.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);.;Loss of helix (P = 0.0376);.;.;.;.;.;
MVP		0.29
MPC		0.70
ClinPred		0.87	D
GERP RS		5.9
Varity_R		0.10
gMVP		0.46

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: chr8-92972615;