21-35119037-T-G

Variant names:

• chr21-35119037-T-G
• rs2834779
• ENST00000475045.6:c.-196-53965A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000475045.6(RUNX1):​c.-196-53965A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 152,120 control chromosomes in the GnomAD database, including 30,280 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.61 (30280 hom., cov: 33)
• Consequence: RUNX1 ENST00000475045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0940
• Publications: 2 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 Gene-Disease associations (from GenCC):

• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000475045.6	c.-196-53965A>C		intron_variant	Intron 9 of 12	5		ENSP00000477072.1

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92883 AN: 152002 Hom.: 30230 Cov.: 33

Gnomad AFR AF: 0.863

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.579

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.611 AC: 92994 AN: 152120 Hom.: 30280 Cov.: 33 AF XY: 0.605 AC XY: 44978 AN XY: 74344

African (AFR) AF: 0.863 AC: 35840 AN: 41542

American (AMR) AF: 0.465 AC: 7102 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 1886 AN: 3470

East Asian (EAS) AF: 0.558 AC: 2881 AN: 5166

South Asian (SAS) AF: 0.531 AC: 2555 AN: 4812

European-Finnish (FIN) AF: 0.518 AC: 5462 AN: 10544

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35325 AN: 67982

Other (OTH) AF: 0.577 AC: 1220 AN: 2116

Alfa AF: 0.534 Hom.: 35277

Bravo AF: 0.623

Asia WGS AF: 0.593 AC: 2064 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.40
DANN	Benign	0.46
PhyloP100		-0.094

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2834779; hg19: chr21-36491334;