rs1569061762

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_001754.5(RUNX1):​c.611G>C​(p.Arg204Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

RUNX1
NM_001754.5 missense, splice_region

Scores

15
3
1
Splicing: ADA: 0.7721
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.90
Variant links:
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]
ENSG00000286153 (HGNC:56821): (RUNX1 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001754.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-34859477-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2177591.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RUNX1NM_001754.5 linkc.611G>C p.Arg204Pro missense_variant, splice_region_variant Exon 6 of 9 ENST00000675419.1 NP_001745.2 Q01196-8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RUNX1ENST00000675419.1 linkc.611G>C p.Arg204Pro missense_variant, splice_region_variant Exon 6 of 9 NM_001754.5 ENSP00000501943.1 Q01196-8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.99
D;.;.;.;.;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D;.;D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D;D
MetaSVM
Pathogenic
0.99
D
MutationAssessor
Uncertain
2.8
M;.;.;.;M;.
PrimateAI
Pathogenic
0.91
D
PROVEAN
Pathogenic
-6.2
D;D;D;D;D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;.
Polyphen
1.0
D;D;D;.;D;.
Vest4
0.95
MutPred
0.72
Loss of MoRF binding (P = 0.0048);.;.;Loss of MoRF binding (P = 0.0048);Loss of MoRF binding (P = 0.0048);.;
MVP
1.0
MPC
1.9
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.98
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.77
dbscSNV1_RF
Benign
0.70
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-36231773; COSMIC: COSV55875973; COSMIC: COSV55875973; API