rs750755857

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PS4_SupportingBP4

This summary comes from the ClinGen Evidence Repository: NM_001754.5(RUNX1):c.35C>T (p.Ser12Leu) is a missense variant. It has a REVEL score <0.50 (0.305) and SpliceAI score of <0.20 (Donor Loss of 0.02 at -23 bp) (BP4). It has been reported in one proband meeting at least one of the RUNX1-phenotype criteria (PS4_Supporting; PMID:34166225). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Panel for RUNX1: BP4, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA410208238/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 5.59

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]

RUNX1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX1	NM_001754.5 link	c.35C>T	p.Ser12Leu	missense_variant	2/9	ENST00000675419.1	NP_001745.2	Q01196-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1 link	c.35C>T	p.Ser12Leu	missense_variant	2/9		NM_001754.5	ENSP00000501943.1		Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251474

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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

AF:

0.00000889

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Jul 07, 2022

NM_001754.5(RUNX1):c.35C>T (p.Ser12Leu) is a missense variant. It has a REVEL score <0.50 (0.305) and SpliceAI score of <0.20 (Donor Loss of 0.02 at -23 bp) (BP4). It has been reported in one proband meeting at least one of the RUNX1-phenotype criteria (PS4_Supporting; PMID: 34166225). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Panel for RUNX1: BP4, PS4_Supporting. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

May 20, 2021

- -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 12 of the RUNX1 protein (p.Ser12Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 34166225). ClinVar contains an entry for this variant (Variation ID: 532661). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Acute myeloid leukemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

.;.;T;.;.

Eigen

Benign

0.099

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.87

D;.;D;D;T

M_CAP

Benign

0.050

MetaRNN

Benign

0.34

T;T;T;T;T

MetaSVM

Uncertain

0.64

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.98

N;N;N;.;D

REVEL

Uncertain

0.30

Sift

Benign

0.085

T;T;T;.;.

Sift4G

Benign

0.067

T;T;D;.;.

Polyphen

0.0030

B;B;.;.;.

Vest4

0.48

MutPred

0.30

Loss of disorder (P = 0.0015);Loss of disorder (P = 0.0015);Loss of disorder (P = 0.0015);Loss of disorder (P = 0.0015);Loss of disorder (P = 0.0015);

MVP

0.96

MPC

0.54

ClinPred

0.99

GERP RS

5.4

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over