rs718387

Variant names:

• chr21-35755779-G-A
• rs718387
• ENST00000475045.6:c.-587-100904C>T

Variant summary

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

The ENST00000475045.6(RUNX1):​c.-587-100904C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 152,094 control chromosomes in the GnomAD database, including 10,602 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 0.26 (10602 hom., cov: 32)
• Consequence: RUNX1 ENST00000475045.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.150
• Publications: 5 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 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.-587-100904C>T		intron_variant	Intron 6 of 12	5		ENSP00000477072.1

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38718 AN: 151976 Hom.: 10566 Cov.: 32

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.303

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0645

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.236

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

GnomAD4 genome AF: 0.255 AC: 38804 AN: 152094 Hom.: 10602 Cov.: 32 AF XY: 0.253 AC XY: 18840 AN XY: 74346

African (AFR) AF: 0.681 AC: 28202 AN: 41430

American (AMR) AF: 0.210 AC: 3207 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 605 AN: 3466

East Asian (EAS) AF: 0.304 AC: 1569 AN: 5162

South Asian (SAS) AF: 0.134 AC: 644 AN: 4816

European-Finnish (FIN) AF: 0.0645 AC: 684 AN: 10600

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.0481 AC: 3272 AN: 68012

Other (OTH) AF: 0.241 AC: 510 AN: 2116

Alfa AF: 0.148 Hom.: 7802

Bravo AF: 0.286

Asia WGS AF: 0.238 AC: 827 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.3
DANN	Benign	0.32
PhyloP100		0.15

Splicing

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

Other links and lift over

dbSNP: rs718387; hg19: chr21-37128077;