Variant rs750495319 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The NM_001754.5(RUNX1):c.1098_1103dup (p.Ile366_Gly367dup) variant has a highest MAF 0.0001618 (11 out of 67990 alleles) in European (non-Finnish) subpopulation of gnomAD v3.1 (BS1). In summary, the clinical significance of this variant is Likely Benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CV239040/MONDO:0011071/008

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

RUNX1
NM_001754.5 inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign reviewed by expert panel U:3B:1

Conservation

PhyloP100: 6.14

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 Likely_benign. Variant got -4 ACMG points.

BS1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5 linkuse as main transcript	c.1103_1104insCGGCAT	p.Ile366_Gly367dup	inframe_insertion	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1 linkuse as main transcript	c.1103_1104insCGGCAT	p.Ile366_Gly367dup	inframe_insertion	9/9		NM_001754.5	A1	Q01196-8

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000749

AC:

AN:

200284

Hom.:

AF XY:

0.0000924

AC XY:

AN XY:

108268

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000337

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000152

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000794

AC:

114

AN:

1435436

Hom.:

Cov.:

AF XY:

0.0000745

AC XY:

AN XY:

711532

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000740

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000605

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000901

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.000105

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000680

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2022	In-frame duplication of 2 amino acids in a non-repeat region; Published functional studies suggest no damaging effect: demonstrated no significant impact on transcriptional activity in one study (Li et al., 2021); Identified in patients with thrombocytopenia and/or leukemia, co-occurring with an ETV6 truncating variant in one family (Kanagal-Shamanna et al., 2017; DiNardo et al., 2018; Karastaneva et al., 2020; Li et al., 2021); Also reported as p.M368delinsIGM, c.1103_1104insCGGCAT; This variant is associated with the following publications: (PMID: 34426522, 29682723, 28659335, 31704777, 34166225) -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This variant, c.1098_1103dup, results in the insertion of 2 amino acid(s) of the RUNX1 protein (p.Ile366_Gly367dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750495319, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of familial platelet disorder with propensity to acute myelogenous leukemia and familial thrombocytopenia (PMID: 27210295, 28659335, 31704777). ClinVar contains an entry for this variant (Variation ID: 239040). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Likely benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

Feb 20, 2021

The NM_001754.5(RUNX1):c.1098_1103dup (p.Ile366_Gly367dup) variant has a highest MAF 0.0001618 (11 out of 67990 alleles) in European (non-Finnish) subpopulation of gnomAD v3.1 (BS1). In summary, the clinical significance of this variant is Likely Benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS1. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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