chr21-34792388-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: This c.1190A>G (p.Gln397Arg) missense variant has a MAF of 0.003624 (0.3624%, 53/14624, 202938 alleles) in the East Asian subpopulation of the gnomAD v2 cohort, which is ≥ 0.0015 (0.15%) (BA1). The high allele frequency accounts for reports of this variant in affected individuals: 2 heterozygous patients with AML (PMID:19808697), a homozygous patient with personal and family history of thrombocytopenia (PMID:30103613), and other reports of this variant in patients with MDS, AML, and T-ALL that have not been confirmed to be of germline origin (PMID:17910630, 24523240, 24792891, 24850867, 28157215, 29279377). Furthermore, an abstract indicated that a dual luciferase assay used to assess this variant's transactivation ability in K562 cells was normal, although this data was not published in a peer-reviewed format (Huang et al., 2009, ASH Abstract 3468 - https://ashpublications.org/blood/article/114/22/3468/132805/High-Frequency-of-C-Terminal-Frame-Shift-Mutations). This missense variant have a REVEL score <0.5 (0.238), and is not predicted by SpliceAI, MES, or SSF-like to have a splicing impact (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014193/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: 5.59

Publications

12 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: Benign. The variant received -9 ACMG points.

BP4

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

BA1

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.1190A>G	p.Gln397Arg	missense_variant	Exon 9 of 9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 link	c.1190A>G	p.Gln397Arg	missense_variant	Exon 9 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes

AF:

0.0000793

AC:

AN:

151324

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00219

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000268

AC:

AN:

171874

AF XY:

0.000207

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00352

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000481

AC:

AN:

1414298

Hom.:

Cov.:

AF XY:

0.0000429

AC XY:

AN XY:

699014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32640

American (AMR)

AF:

0.00

AC:

AN:

36988

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25290

East Asian (EAS)

AF:

0.00163

AC:

AN:

37416

South Asian (SAS)

AF:

0.00

AC:

AN:

80552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00000276

AC:

AN:

1087468

Other (OTH)

AF:

0.0000683

AC:

AN:

58590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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

AF:

0.0000792

AC:

AN:

151448

Hom.:

Cov.:

AF XY:

0.0000810

AC XY:

AN XY:

74042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41298

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00219

AC:

AN:

5018

South Asian (SAS)

AF:

0.00

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67776

Other (OTH)

AF:

0.000476

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000480

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000103

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Jun 28, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Dec 07, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in the germline of an individual with pediatric ALL (Cecile Liu et al., 2022); This variant is associated with the following publications: (PMID: 24523240, Liu2022, 19808697, Huang_2009_Abstract) -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

Jul 07, 2022

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

This c.1190A>G (p.Gln397Arg) missense variant has a MAF of 0.003624 (0.3624%, 53/14624, 202938 alleles) in the East Asian subpopulation of the gnomAD v2 cohort, which is ≥ 0.0015 (0.15%) (BA1). The high allele frequency accounts for reports of this variant in affected individuals: 2 heterozygous patients with AML (PMID: 19808697), a homozygous patient with personal and family history of thrombocytopenia (PMID: 30103613), and other reports of this variant in patients with MDS, AML, and T-ALL that have not been confirmed to be of germline origin (PMID: 17910630, 24523240, 24792891, 24850867, 28157215, 29279377). Furthermore, an abstract indicated that a dual luciferase assay used to assess this variant's transactivation ability in K562 cells was normal, although this data was not published in a peer-reviewed format (Huang et al., 2009, ASH Abstract 3468 - https://ashpublications.org/blood/article/114/22/3468/132805/High-Frequency-of-C-Terminal-Frame-Shift-Mutations). This missense variant have a REVEL score <0.5 (0.238), and is not predicted by SpliceAI, MES, or SSF-like to have a splicing impact (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1 and BP4. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;.;.;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;.;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.0

M;.;.;.

PhyloP100

5.6

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.9

D;D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Benign

0.37

T;T;T;T

Polyphen

0.98

D;P;P;.

Vest4

0.57

MutPred

0.65

Gain of methylation at Q370 (P = 0.0245);.;.;.;

MVP

0.57

MPC

1.1

ClinPred

0.20

GERP RS

5.1

Varity_R

0.52

gMVP

0.86

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over