rs1060502574

chr21-34834410-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001754.5(RUNX1):c.805G>C(p.Asp269His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,457,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.805G>C	p.Asp269His	missense_variant, splice_region_variant	7/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.805G>C	p.Asp269His	missense_variant, splice_region_variant	7/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457940 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724384

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 22, 2018

This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with histidine at codon 269 of the RUNX1 protein (p.Asp269His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant also falls at the last nucleotide of exon 7 of the RUNX1 coding sequence, which is part of the consensus splice site for this exon. This variant has not been reported in the literature in individuals with RUNX1-related disease. ClinVar contains an entry for this variant (Variation ID: 409807). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	30
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.;.
Eigen	Benign	-0.0071
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;.
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Pathogenic	1.2	D
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.065	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.63
MutPred		0.12		Loss of phosphorylation at T243 (P = 0.1803);.;.;
MVP		0.81
MPC		1.6
ClinPred		0.95	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.080		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: rs1060502574; hg19: chr21-36206707;