Variant 8-91991855-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000523629.6(RUNX1T1):c.775C>T(p.His259Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RUNX1T1
ENST00000523629.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

Variant links:

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 links:

RUNX1T1 (HGNC:):

RUNX1T1 links:

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ACMG classification

Classification made for transcript

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/exons	Protein	UniProt
RUNX1T1	NM_001198679.3 linkuse as main transcript	c.952C>T	p.His318Tyr	missense_variant	7/12	NP_001185608.1	Q06455A0A0A0MSU1
RUNX1T1	NM_001395209.1 linkuse as main transcript	c.859C>T	p.His287Tyr	missense_variant	7/12	NP_001382138.1
RUNX1T1	NM_001198634.2 linkuse as main transcript	c.808C>T	p.His270Tyr	missense_variant	6/11	NP_001185563.1	Q06455-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1T1	ENST00000523629.6 linkuse as main transcript	c.775C>T	p.His259Tyr	missense_variant	7/12	5		ENSP00000428543.1		Q06455-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251344

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.952C>T (p.H318Y) alteration is located in exon 7 (coding exon 7) of the RUNX1T1 gene. This alteration results from a C to T substitution at nucleotide position 952, causing the histidine (H) at amino acid position 318 to be replaced by a tyrosine (Y). 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

Uncertain

0.045

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

.;D;D;.;D;D;.;D;.;.;.;.;.

Eigen

Uncertain

0.61

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;.;.;D;.;D;D;.;.;.;D;D;.

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.54

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.9

.;L;L;.;L;L;.;L;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.1

.;.;.;.;.;N;.;N;N;N;N;.;N

REVEL

Uncertain

0.32

Sift

Benign

0.53

.;.;.;.;.;T;.;T;T;T;T;.;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.99

D;P;P;.;P;P;.;P;D;.;.;.;D

Vest4

0.77

MutPred

0.16

.;Gain of phosphorylation at H259 (P = 0.0043);Gain of phosphorylation at H259 (P = 0.0043);.;Gain of phosphorylation at H259 (P = 0.0043);Gain of phosphorylation at H259 (P = 0.0043);.;Gain of phosphorylation at H259 (P = 0.0043);.;.;.;.;.;

MVP

0.51

MPC

1.6

ClinPred

0.58

GERP RS

6.1

Varity_R

0.18

gMVP

0.49

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over