rs201164283

chr21-34799444-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001754.5(RUNX1):c.824C>T(p.Pro275Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P275S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 9.17

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042799175).
• BP6: Variant 21-34799444-G-A is Benign according to our data. Variant chr21-34799444-G-A is described in ClinVar as [Benign]. Clinvar id is 464009.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAdExome at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.824C>T	p.Pro275Leu	missense_variant	8/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.824C>T	p.Pro275Leu	missense_variant	8/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 251480 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461828 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74492

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000136 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000214 AC: 26

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 14, 2023	- -
Benign, reviewed by expert panel	curation	ClinGen Myeloid Malignancy Variant Curation Expert Panel	Aug 02, 2019	The NM_001754.4:c.824C>T (p.Pro275Leu) variant has an MAF of 0.00225 (0.2%, 26/11566 alleles) in the Latino subpopulation of the ExAC cohort that is >/= 0.0015 (0.15%) (BA1). This missense variant has a REVEL score <0.15 (0.146) and SSF and MES predict either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created (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, BP4. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;.;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.043	T;T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D;D;D;T
Sift4G	Uncertain	0.012	D;D;D;T
Polyphen		0.041	B;B;B;.
Vest4		0.57
MVP		0.73
MPC		0.75
ClinPred		0.22	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201164283; hg19: chr21-36171741;