rs375989348

chr21-34792509-G-Cchr21-34792509-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001754.5(RUNX1):c.1069C>G(p.Pro357Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. P357S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.02

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2223751).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.1069C>G	p.Pro357Ala	missense_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.1069C>G	p.Pro357Ala	missense_variant	9/9		NM_001754.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000451 AC: 1 AN: 221630 Hom.: 0 AF XY: 0.00000830 AC XY: 1 AN XY: 120494

Gnomad AFR exome AF: 0.0000726

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449890 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 719948

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.77	D;.;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;.;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.77	N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.21
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.29	B;B;B;.
Vest4		0.36
MutPred		0.39		Gain of relative solvent accessibility (P = 0.0082);.;.;.;
MVP		0.74
MPC		0.65
ClinPred		0.35	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.58

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: rs375989348; hg19: chr21-36164806;