8-91960318-A-C

Variant names:

• chr8-91960318-A-C
• rs1810154337
• NM_175634.3:c.1739T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175634.3(RUNX1T1):​c.1739T>G​(p.Met580Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. M580T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RUNX1T1 NM_175634.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.38
• Publications: 0 publications found

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]

RUNX1T1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, PanelApp Australia

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=0.10496265).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175634.3. 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
	RUNX1T1	NM_175634.3	MANE Select	c.1739T>G	p.Met580Arg	missense	Exon 12 of 12	NP_783552.1	Q06455-1
	RUNX1T1	NM_001198679.3		c.1916T>G	p.Met639Arg	missense	Exon 12 of 12	NP_001185608.1	A0A0A0MSU1
	RUNX1T1	NM_001395209.1		c.1823T>G	p.Met608Arg	missense	Exon 12 of 12	NP_001382138.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1T1	ENST00000523629.7	TSL:5 MANE Select	c.1739T>G	p.Met580Arg	missense	Exon 12 of 12	ENSP00000428543.1	Q06455-1
	RUNX1T1	ENST00000396218.5	TSL:1	c.1658T>G	p.Met553Arg	missense	Exon 11 of 11	ENSP00000379520.1	Q06455-2
	RUNX1T1	ENST00000518844.5	TSL:1	c.1658T>G	p.Met553Arg	missense	Exon 15 of 15	ENSP00000430728.1	Q06455-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459460 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725820

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111078

Other (OTH) AF: 0.00 AC: 0 AN: 60230

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.86
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.099
Sift	Benign	0.054	T
Sift4G	Benign	0.55	T
Polyphen		0.016	B
Vest4		0.25
MutPred		0.12		Loss of solvent accessibility (P = 0.0595)
MVP		0.13
MPC		1.0
ClinPred		0.44	T
GERP RS		5.9
Varity_R		0.54
gMVP		0.30
Mutation Taster		=72/28	polymorphism

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: rs1810154337; hg19: chr8-92972546;