21-34880696-A-T

Variant names:

• chr21-34880696-A-T
• rs768100078
• NM_001754.5:c.369T>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. BP7 BP4 PM1_Supporting

This summary comes from the ClinGen Evidence Repository: In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM1_Supporting LINK:https://erepo.genome.network/evrepo/ui/classification/CA10014523/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RUNX1 NM_001754.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:1
• Conservation: PhyloP100: -2.36
• Publications: 0 publications found

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-AS1 (HGNC:56821): (RUNX1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX1	NM_001754.5	c.369T>A	p.Asp123Glu	missense_variant	Exon 5 of 9	ENST00000675419.1	NP_001745.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000675419.1	c.369T>A	p.Asp123Glu	missense_variant	Exon 5 of 9		NM_001754.5	ENSP00000501943.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251394 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000205 AC: 3 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Apr 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 123 of the RUNX1 protein (p.Asp123Glu). This variant is present in population databases (rs768100078, gnomAD 0.009%). 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: 463993). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RUNX1 protein function with a negative predictive value of 80%. 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. -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Nov 13, 2023

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4, BP7, PM1_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	0.36
DANN	Benign	0.69
DEOGEN2	Pathogenic	0.92	D;.;.;.;.;.;D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.73	T;T;.;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.018	D
MutationAssessor	Benign	0.23	N;.;.;.;N;.;.
PhyloP100		-2.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.58	T;T;T;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;T;.;T
Polyphen		0.0020	B;B;B;.;B;.;.
Vest4		0.28
MutPred		0.48		Gain of sheet (P = 0.0827);.;.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;
MVP		0.58
MPC		0.59
ClinPred		0.054	T
GERP RS		-10
Varity_R		0.31
gMVP		0.56
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs768100078; hg19: chr21-36252993;