21-34892925-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.97G>A (p.Asp33Asn) is a missense variant has a SpliceAI score ≥ 0.38 (Acceptor Loss: 0.68; Donor Loss: 0.76) and is predicted to impact splicing (PP3). 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: PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014629/MONDO:0011071/008

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense, splice_region

Scores

Splicing: ADA: 0.9997

Clinical Significance

Uncertain significance reviewed by expert panel U:3

Conservation

PhyloP100: 0.0760

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5 link	c.97G>A	p.Asp33Asn	missense_variant, splice_region_variant	Exon 3 of 9	ENST00000675419.1	NP_001745.2	Q01196-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 link	c.97G>A	p.Asp33Asn	missense_variant, splice_region_variant	Exon 3 of 9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249294

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000214

AC:

AN:

1399174

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699648

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32220

American (AMR)

AF:

0.0000225

AC:

AN:

44438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25676

East Asian (EAS)

AF:

0.00

AC:

AN:

39266

South Asian (SAS)

AF:

0.00

AC:

AN:

84218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.00000189

AC:

AN:

1056046

Other (OTH)

AF:

0.00

AC:

AN:

58310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.018321), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 14, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.97G>A variant (also known as p.D33N), located in coding exon 2 of the RUNX1 gene, results from a G to A substitution at nucleotide position 97. The amino acid change results in aspartic acid to asparagine at codon 33, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is well conserved in available vertebrate species. This amino acid position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in a splice defect involving exons excluded from naturally occurring transcripts; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). In addition, as a missense, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Sep 25, 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.97G>A (p.Asp33Asn) is a missense variant has a SpliceAI score ≥ 0.38 (Acceptor Loss: 0.68; Donor Loss: 0.76) and is predicted to impact splicing (PP3). 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: PP3. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Jun 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 409811). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown this missense change is associated with skipping of exon 3, but one or more of the resulting mRNA isoform(s) may be naturally occurring (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This missense change has been observed in individual(s) with clinical features of thrombocytopenia (PMID: 32208489). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 33 of the RUNX1 protein (p.Asp33Asn). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is present in population databases (rs781761402, gnomAD 0.003%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.58

T;.;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Pathogenic

0.95

PhyloP100

0.076

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.8

D;D;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.0040

D;D;.

Sift4G

Benign

0.14

T;T;.

Polyphen

1.0

D;D;.

Vest4

0.15

MutPred

0.42

Loss of phosphorylation at S35 (P = 0.1114);Loss of phosphorylation at S35 (P = 0.1114);Loss of phosphorylation at S35 (P = 0.1114);

MVP

1.0

MPC

1.6

ClinPred

0.91

GERP RS

1.4

gMVP

0.64

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.86

SpliceAI score (max)

0.76

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.76

Position offset: 0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over