8-92014728-A-T

Position:

• chr8-92014728-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000523629.6(RUNX1T1):​c.319T>A​(p.Ser107Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RUNX1T1 ENST00000523629.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32687783).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1T1	NM_001198679.3	c.496T>A	p.Ser166Thr	missense_variant	4/12		NP_001185608.1
RUNX1T1	NM_001395209.1	c.403T>A	p.Ser135Thr	missense_variant	4/12		NP_001382138.1
RUNX1T1	NM_001198634.2	c.352T>A	p.Ser118Thr	missense_variant	3/11		NP_001185563.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1T1	ENST00000523629.6	c.319T>A	p.Ser107Thr	missense_variant	4/12	5		ENSP00000428543.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.496T>A (p.S166T) alteration is located in exon 4 (coding exon 4) of the RUNX1T1 gene. This alteration results from a T to A substitution at nucleotide position 496, causing the serine (S) at amino acid position 166 to be replaced by a threonine (T). 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	0.11
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;T;T;.;T;T;.;T;.;.;.;.;.;T;T;T;T;T;T;T;.;T;.;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D;.;.;D;.;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	.;L;L;.;L;L;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.83	.;.;.;.;.;N;.;N;N;N;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.080
Sift	Benign	0.19	.;.;.;.;.;T;.;T;T;T;T;.;T;T;T;T;D;D;D;D;D;T;T;D;D
Sift4G	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;T;.;T;.;.;.;.;.;.
Polyphen		0.34	B;P;P;.;P;P;.;P;B;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.42
MutPred		0.27		.;Loss of phosphorylation at S107 (P = 0.033);Loss of phosphorylation at S107 (P = 0.033);.;Loss of phosphorylation at S107 (P = 0.033);Loss of phosphorylation at S107 (P = 0.033);.;Loss of phosphorylation at S107 (P = 0.033);.;.;.;.;.;.;Loss of phosphorylation at S107 (P = 0.033);.;Loss of phosphorylation at S107 (P = 0.033);.;Loss of phosphorylation at S107 (P = 0.033);Loss of phosphorylation at S107 (P = 0.033);.;.;.;Loss of phosphorylation at S107 (P = 0.033);Loss of phosphorylation at S107 (P = 0.033);
MVP		0.65
MPC		0.76
ClinPred		0.87	D
GERP RS		6.0
Varity_R		0.20
gMVP		0.50

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: chr8-93026956;