Variant chr21-34788691-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP2BS1

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.*3444A>G is an intronic variant. MAF of 0.001 (0.1%, 18/15,276 alleles) in the Latino/Admixed American subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.00015 (0.015%) (BS1). This variant is reported in 4 homozygotes in gnomAD v2.1.1 (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1 and BP2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA10653547/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0021 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 3_prime_UTR

Scores

Clinical Significance

Likely benign reviewed by expert panel B:2

Conservation

PhyloP100: 0.885

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP2

BS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.*3444A>G		3_prime_UTR_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.*3444A>G	3_prime_UTR_variant	9/9		NM_001754.5	A1	Q01196-8
RUNX1	ENST00000300305.7 linkuse as main transcript	c.*3444A>G	3_prime_UTR_variant	8/8	1		A1	Q01196-8
RUNX1	ENST00000344691.8 linkuse as main transcript	c.*3444A>G	3_prime_UTR_variant	6/6	1		P4	Q01196-1
RUNX1	ENST00000437180.5 linkuse as main transcript	c.*3444A>G	3_prime_UTR_variant	9/9	5		A1	Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.00209

AC:

318

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0223

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000617

Gnomad OTH

AF:

0.00192

GnomAD4 exome

AF:

0.000640

AC:

AN:

81190

Hom.:

Cov.:

AF XY:

0.000829

AC XY:

AN XY:

37376

show subpopulations

Gnomad4 AFR exome

AF:

0.000515

Gnomad4 AMR exome

AF:

0.00240

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0227

Gnomad4 NFE exome

AF:

0.000240

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.00209

AC:

318

AN:

152292

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

213

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0223

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.000790

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jul 08, 2022

NM_001754.5(RUNX1):c.*3444A>G is an intronic variant. MAF of 0.001 (0.1%, 18/15,276 alleles) in the Latino/Admixed American subpopulation of the gnomAD v3.1.2 cohort is ≥ 0.00015 (0.015%) (BS1). This variant is reported in 4 homozygotes in gnomAD v2.1.1 (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1 and BP2 -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

3.7

DANN

Benign

0.77

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