chr21-34788691-T-C

Position:

• chr21-34788691-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP2 BS1

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
• Clinical Significance: Likely benign reviewed by expert panel B:2
• Conservation: PhyloP100: 0.885

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.*3444A>G		3_prime_UTR_variant	9/9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.*3444A>G		3_prime_UTR_variant	9/9		NM_001754.5	ENSP00000501943	A1
RUNX1	ENST00000300305.7	c.*3444A>G		3_prime_UTR_variant	8/8	1		ENSP00000300305	A1
RUNX1	ENST00000344691.8	c.*3444A>G		3_prime_UTR_variant	6/6	1		ENSP00000340690	P4
RUNX1	ENST00000437180.5	c.*3444A>G		3_prime_UTR_variant	9/9	5		ENSP00000409227	A1

Frequencies

GnomAD3 genomes AF: 0.00209 AC: 318 AN: 152174 Hom.: 4 Cov.: 32

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: 52 AN: 81190 Hom.: 0 Cov.: 0 AF XY: 0.000829 AC XY: 31 AN XY: 37376

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.: 4 Cov.: 32 AF XY: 0.00286 AC XY: 213 AN XY: 74466

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.: 0

Bravo AF: 0.000790

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

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

Other links and lift over

dbSNP: rs183666715; hg19: chr21-36160988;