rs202068364

Positions:

• chr21-34792325-A-G
• chr21-34792325-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_001754.5(RUNX1):​c.1253T>C​(p.Met418Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000403 in 1,241,458 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000040 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.64

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.1253T>C	p.Met418Thr	missense_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.1253T>C	p.Met418Thr	missense_variant	9/9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000403 AC: 5 AN: 1241458 Hom.: 0 Cov.: 36 AF XY: 0.00000328 AC XY: 2 AN XY: 610680

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000513

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.86	D;D;.;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.74	D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.1	M;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.4	D;D;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.26	B;D;D;.
Vest4		0.65
MutPred		0.60		Loss of sheet (P = 0.0025);.;.;.;
MVP		0.57
MPC		1.0
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.83

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: rs202068364; hg19: chr21-36164622;