chr21-35048844-C-T

Position:

chr21-35048844-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: NM_001754.4(RUNX1):c.56G>A (p.Arg19Lys) is a missense variant predicted to cause substitution of arginine by lysine at amino acid 19 (p.R19K); note that this variant is in the 5' UTR, c.-161732G>A, of NM_001001890.3. The variant has been reported in a 69-year-old patient with NPM1-mutated, cytogenetically normal AML at a VAF=53% (PMID:31367767) and in a patient with CMML (PMID:24030381, Supplementary Table 2); however, germline origin is unclear for these cases. The highest population minor allele frequency in gnomAD v2 is 0.006966% (9/129192 alleles) in the non-Finnish European population, and the variant has also been reported in 1/1358 controls from a study evaluating 57 individuals with cutaneous melanoma and 2 other primaries (PMID:29641532, Supplementary Table 3). To our knowledge, functional assays have not been reported for this variant, but the computational predictor REVEL gives a score of 0.456, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy-VCEP: BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014724/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 missense, splice_region

Scores

Splicing: ADA: 0.0006851

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.75

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 -1 ACMG points.

BP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.56G>A	p.Arg19Lys	missense_variant, splice_region_variant	2/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.56G>A	p.Arg19Lys	missense_variant, splice_region_variant	2/9		NM_001754.5	A1	Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152148

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251478

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461138

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

726928

show subpopulations

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:

0.0000873

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 28, 2020

DNA sequence analysis of the RUNX1 gene demonstrated a sequence change, c.56G>A, in exon 2 that results in an amino acid change, p.Arg19Lys. This sequence change does not appear to have been previously described in patients with RUNX1-related disorders and has been described in the gnomAD database with a low population frequency of 0.0032% (dbSNP rs759078185). The p.Arg19Lys change affects a poorly conserved amino acid residue located in a domain of the RUNX1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg19Lys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg19Lys change remains unknown at this time. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 05, 2023

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 19 of the RUNX1 protein (p.Arg19Lys). This variant is present in population databases (rs759078185, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RUNX1-related conditions. ClinVar contains an entry for this variant (Variation ID: 409814). 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

Mar 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Benign

0.24

.;.;T;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.44

T;.;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.60

D;D;D;D;D

MetaSVM

Uncertain

0.70

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.38

N;N;N;.;D

REVEL

Uncertain

0.46

Sift

Benign

0.13

T;T;T;.;.

Sift4G

Benign

0.48

T;T;T;.;.

Polyphen

0.90

P;P;.;.;.

Vest4

0.67

MutPred

0.39

Gain of ubiquitination at R19 (P = 0.0267);Gain of ubiquitination at R19 (P = 0.0267);Gain of ubiquitination at R19 (P = 0.0267);Gain of ubiquitination at R19 (P = 0.0267);Gain of ubiquitination at R19 (P = 0.0267);

MVP

0.94

MPC

0.73

ClinPred

0.95

GERP RS

5.2

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00069

dbscSNV1_RF

Benign

0.010

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

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