21-34887027-A-G

Variant names:

• chr21-34887027-A-G
• rs111527738
• NM_001754.5:c.167T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BS3 BP2 BA1

This summary comes from the ClinGen Evidence Repository: The NM_001754.4:c.167T>C (p.Leu56Ser) variant has a MAF of 0.03259 (3.259%, 518/15,894 alleles) in the South Asian subpopulation of the ExAC cohort that is ≥ 0.0015 (0.15%) (BA1). This variant is detected in homozygous state (56) in gnomAD population database (BP2). Transactivation assays demonstrating normal transactivation (80-115% of wt) and data from secondary assays demonstrate normal DNA binding, CBFβ binding and sub-cellular localization (BS3; PMID:23817177). Two patients reported in PMID:29365323 with AML. But PS4 can not apply in combined with BA1. 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, BS3, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014578/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 32)
  • Exomes 𝑓: 0.019 (357 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:1 B:15
• Conservation: PhyloP100: 3.34
• Publications: 48 publications found

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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, G2P
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.167T>C	p.Leu56Ser	missense	Exon 4 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.86T>C	p.Leu29Ser	missense	Exon 1 of 6	NP_001001890.1	Q01196-1
	RUNX1	NM_001122607.2		c.86T>C	p.Leu29Ser	missense	Exon 1 of 5	NP_001116079.1	Q01196-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.167T>C	p.Leu56Ser	missense	Exon 4 of 9	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.167T>C	p.Leu56Ser	missense	Exon 3 of 8	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.86T>C	p.Leu29Ser	missense	Exon 1 of 6	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1926 AN: 152200 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0176

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0152 AC: 3522 AN: 231814 AF XY: 0.0169

Gnomad AFR exome AF: 0.00264

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.00175

Gnomad EAS exome AF: 0.000113

Gnomad FIN exome AF: 0.0147

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0185

GnomAD4 exome AF: 0.0188 AC: 27188 AN: 1449220 Hom.: 357 Cov.: 35 AF XY: 0.0191 AC XY: 13804 AN XY: 721180

African (AFR) AF: 0.00248 AC: 83 AN: 33402

American (AMR) AF: 0.0113 AC: 505 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26054

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39610

South Asian (SAS) AF: 0.0308 AC: 2650 AN: 86120

European-Finnish (FIN) AF: 0.0167 AC: 716 AN: 42812

Middle Eastern (MID) AF: 0.0215 AC: 124 AN: 5762

European-Non Finnish (NFE) AF: 0.0197 AC: 21897 AN: 1110748

Other (OTH) AF: 0.0193 AC: 1158 AN: 60152

GnomAD4 genome AF: 0.0126 AC: 1925 AN: 152314 Hom.: 20 Cov.: 32 AF XY: 0.0125 AC XY: 933 AN XY: 74472

African (AFR) AF: 0.00385 AC: 160 AN: 41572

American (AMR) AF: 0.0168 AC: 257 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0302 AC: 146 AN: 4828

European-Finnish (FIN) AF: 0.0112 AC: 119 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0176 AC: 1198 AN: 68014

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0162 Hom.: 40

Bravo AF: 0.0122

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00275 AC: 12

ESP6500EA AF: 0.0146 AC: 124

ExAC AF: 0.0148 AC: 1760

Asia WGS AF: 0.0120 AC: 43 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	6	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (7)
-	-	5	not provided (5)
1	-	1	Acute myeloid leukemia (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	RUNX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0049	T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	0.93	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.31
Sift	Benign	0.51	T
Sift4G	Benign	0.44	T
Polyphen		1.0	D
Vest4		0.088
MPC		1.7
ClinPred		0.068	T
GERP RS		5.0
PromoterAI		0.021	Neutral
Varity_R		0.17
gMVP		0.66

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

Other links and lift over

dbSNP: rs111527738; hg19: chr21-36259324; COSMIC: COSV55866281; COSMIC: COSV55866281;