21-34859316-G-A

Variant names:

• chr21-34859316-G-A
• rs56138997
• NM_001754.5:c.613+158C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4 BP2 BA1 BP7

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.613+158C>T is an intronic variant which has a MAF of 0.03363 (3.4%, 595/17690 alleles) in the African subpopulation of the gnomAD v2 cohort, meeting the threshold of ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in an individual or in a population database (gnomAD v2) (BP2). It has a SpliceAI score ≤ 0.20 (0.0) (BP4), and evolutionary conservation algorithms predict the site as not being conserved, with a PhyloP score ≤ 2.0 (-0.58) (BP7). 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: BA1, BP2, BP4, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014432/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.021 (44 hom., cov: 33)
  • Exomes 𝑓: 0.017 (101 hom.)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -0.475

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]

ENSG00000286153 (HGNC:56821): (RUNX1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: 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	c.613+158C>T		intron_variant	Intron 6 of 8	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.613+158C>T		intron_variant	Intron 6 of 8		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3130 AN: 152192 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0338

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0235

GnomAD3 exomes AF: 0.0157 AC: 1808 AN: 115162 Hom.: 24 AF XY: 0.0149 AC XY: 873 AN XY: 58680

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0337

Gnomad EAS exome AF: 0.000180

Gnomad SAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00650

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0173 AC: 8773 AN: 507634 Hom.: 101 Cov.: 5 AF XY: 0.0172 AC XY: 4636 AN XY: 269672

Gnomad4 AFR exome AF: 0.0330

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.0348

Gnomad4 EAS exome AF: 0.0000616

Gnomad4 SAS exome AF: 0.0138

Gnomad4 FIN exome AF: 0.00734

Gnomad4 NFE exome AF: 0.0194

Gnomad4 OTH exome AF: 0.0211

GnomAD4 genome AF: 0.0206 AC: 3137 AN: 152310 Hom.: 44 Cov.: 33 AF XY: 0.0196 AC XY: 1457 AN XY: 74488

Gnomad4 AFR AF: 0.0304

Gnomad4 AMR AF: 0.0145

Gnomad4 ASJ AF: 0.0338

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.0198

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0207 Hom.: 18

Bravo AF: 0.0219

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Aug 28, 2024

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_001754.5(RUNX1):c.613+158C>T is an intronic variant which has a MAF of 0.03363 (3.4%, 595/17690 alleles) in the African subpopulation of the gnomAD v2 cohort, meeting the threshold of ≥ 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in an individual or in a population database (gnomAD v2) (BP2). It has a SpliceAI score ≤ 0.20 (0.0) (BP4), and evolutionary conservation algorithms predict the site as not being conserved, with a PhyloP score ≤ 2.0 (-0.58) (BP7). 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: BA1, BP2, BP4, BP7. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.3
DANN	Benign	0.49

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: rs56138997; hg19: chr21-36231613;