rs749004431

Variant names:

• chr21-34834566-C-G
• rs749004431
• NM_001754.5:c.649G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-34834566-C-G
• chr21-34834566-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001754.5(RUNX1):​c.649G>C​(p.Gly217Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000813 in 1,229,798 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G217A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18
• Publications: 0 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: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.649G>C	p.Gly217Arg	missense_variant	Exon 7 of 9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.649G>C	p.Gly217Arg	missense_variant	Exon 7 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.13e-7 AC: 1 AN: 1229798 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 609846

African (AFR) AF: 0.00 AC: 0 AN: 26624

American (AMR) AF: 0.00 AC: 0 AN: 37746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17396

East Asian (EAS) AF: 0.00 AC: 0 AN: 18444

South Asian (SAS) AF: 0.00 AC: 0 AN: 84156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3622

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 963704

Other (OTH) AF: 0.00 AC: 0 AN: 44872

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;.;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M;.;.;M;.
PhyloP100		6.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-2.7	D;D;D;N;N
REVEL	Uncertain	0.62
Sift	Benign	0.059	T;D;D;D;D
Sift4G	Benign	0.39	T;T;T;T;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.89
MutPred		0.21		Loss of ubiquitination at K188 (P = 0.0148);.;.;Loss of ubiquitination at K188 (P = 0.0148);.;
MVP		0.95
MPC		1.7
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.33
gMVP		0.56
Mutation Taster		=69/31	polymorphism

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: rs749004431; hg19: chr21-36206863;