chr21-35718977-A-G

Variant names:

• chr21-35718977-A-G
• rs2835104
• ENST00000475045.6:c.-587-64102T>C

Variant summary

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

The ENST00000475045.6(RUNX1):​c.-587-64102T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 152,118 control chromosomes in the GnomAD database, including 30,333 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 0.62 (30333 hom., cov: 32)
• Consequence: RUNX1 ENST00000475045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• 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

ENSG00000230794 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.83 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.-587-64102T>C		intron_variant	Intron 6 of 12	5		ENSP00000477072.1
ENSG00000230794	ENST00000412240.2	n.105-5530T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93536 AN: 152000 Hom.: 30281 Cov.: 32

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.615

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

GnomAD4 genome AF: 0.616 AC: 93647 AN: 152118 Hom.: 30333 Cov.: 32 AF XY: 0.614 AC XY: 45677 AN XY: 74362

African (AFR) AF: 0.838 AC: 34776 AN: 41512

American (AMR) AF: 0.598 AC: 9136 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2033 AN: 3472

East Asian (EAS) AF: 0.495 AC: 2561 AN: 5172

South Asian (SAS) AF: 0.501 AC: 2413 AN: 4820

European-Finnish (FIN) AF: 0.527 AC: 5562 AN: 10558

Middle Eastern (MID) AF: 0.711 AC: 209 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35312 AN: 67978

Other (OTH) AF: 0.619 AC: 1309 AN: 2114

Alfa AF: 0.568 Hom.: 4341

Bravo AF: 0.633

Asia WGS AF: 0.501 AC: 1743 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.78
PhyloP100		1.1

Splicing

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

Other links and lift over

dbSNP: rs2835104; hg19: chr21-37091275;