chr21-34792191-G-T

Position:

• chr21-34792191-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001754.5(RUNX1):​c.1387C>A​(p.Pro463Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P463P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.24

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.1387C>A	p.Pro463Thr	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.1387C>A	p.Pro463Thr	missense_variant	9/9		NM_001754.5	ENSP00000501943	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385328 Hom.: 0 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 684330

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000276

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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;.;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Benign	0.093	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.51
MutPred		0.76		Gain of relative solvent accessibility (P = 0.0289);.;.;.;
MVP		0.88
MPC		1.7
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.76
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

Publications

LitVar

Other links and lift over

dbSNP: rs868387185; hg19: chr21-36164488;