ENST00000344691.8:c.-4_-2delTGT

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.98-20_98-18del is an intronic variant which has a SpliceAI Δ score ≤ 0.20 (0.00 except for 0.05 at acceptor gain) (BP4). It is completely absent from all population databases (gnomAD v2.1.1, gnomAD v3.1.2, and ExAC v1.0) with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA658799414/MONDO:0011071/008

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RUNX1
ENST00000344691.8 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:1

Conservation

PhyloP100: 8.13

Publications

0 publications found

Variant links:

Genes affected

RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RUNX1 Gene-Disease associations (from GenCC):

hereditary thrombocytopenia and hematologic cancer predisposition syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
acute myeloid leukemia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

RUNX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000344691.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RUNX1	NM_001754.5	MANE Select	c.98-20_98-18delTGT	intron	N/A	NP_001745.2
RUNX1	NM_001001890.3		c.-4_-2delTGT	5_prime_UTR	Exon 1 of 6	NP_001001890.1
RUNX1	NM_001122607.2		c.-4_-2delTGT	5_prime_UTR	Exon 1 of 5	NP_001116079.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RUNX1	ENST00000344691.8	TSL:1	c.-4_-2delTGT	5_prime_UTR	Exon 1 of 6	ENSP00000340690.4
RUNX1	ENST00000358356.9	TSL:1	c.-4_-2delTGT	5_prime_UTR	Exon 1 of 5	ENSP00000351123.5
RUNX1	ENST00000675419.1	MANE Select	c.98-20_98-18delTGT	intron	N/A	ENSP00000501943.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445734

Hom.:

AF XY:

0.00000139

AC XY:

AN XY:

719616

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37732

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111824

Other (OTH)

AF:

0.00

AC:

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 30, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.-4_-2del variant in RUNX1 (NM_001001890.2) has not been previously reporte d in individuals with familial platelet disorder with propensity to myeloid mali gnancy (FPD/AML) and is absent from large population studies. This variant occur s in the 5' untranslated region (5'UTR) of this transcript, and lies within the Kozak consensus sequence which is a cis-regulatory element important for the in tiation of protein translation. In addition, the nucleotide positions impacted b y this deletion are highly conserved in mammals and evolutionarily distant speci es. While this data suggests that the variant may not be tolerated, it is not pr edictive enough to determine its impact on protein translation or to assume path ogenicity. In summary, the clinical significance of the c.-4_-2del variant is un certain.

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Aug 12, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

NM_001754.5(RUNX1):c.98-20_98-18del is an intronic variant which has a SpliceAI Δ score ≤ 0.20 (0.00 except for 0.05 at acceptor gain) (BP4). It is completely absent from all population databases (gnomAD v2.1.1, gnomAD v3.1.2, and ExAC v1.0) with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, PM2_Supporting.

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:1

Sep 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over