rs2835189

Variant names:

• chr21-35969823-T-G
• rs2835189
• ENST00000460207.1:n.437+252A>C

Variant summary

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

The ENST00000460207.1(RUNX1):​n.437+252A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 152,194 control chromosomes in the GnomAD database, including 1,199 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 0.11 (1199 hom., cov: 32)
• Consequence: RUNX1 ENST00000460207.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0980
• 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

LOC101928269 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC101928269	NR_110418.1	n.664+252A>C		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX1	ENST00000460207.1	n.437+252A>C		intron_variant	Intron 3 of 3	1
RUNX1	ENST00000475045.6	c.-771+252A>C		intron_variant	Intron 5 of 12	5		ENSP00000477072.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17064 AN: 152076 Hom.: 1196 Cov.: 32

Gnomad AFR AF: 0.0361

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.0860

Gnomad EAS AF: 0.0713

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.111

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

GnomAD4 genome AF: 0.112 AC: 17079 AN: 152194 Hom.: 1199 Cov.: 32 AF XY: 0.114 AC XY: 8462 AN XY: 74402

African (AFR) AF: 0.0360 AC: 1496 AN: 41544

American (AMR) AF: 0.163 AC: 2488 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0860 AC: 298 AN: 3464

East Asian (EAS) AF: 0.0708 AC: 367 AN: 5180

South Asian (SAS) AF: 0.223 AC: 1075 AN: 4816

European-Finnish (FIN) AF: 0.150 AC: 1586 AN: 10580

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9485 AN: 67998

Other (OTH) AF: 0.113 AC: 239 AN: 2116

Alfa AF: 0.129 Hom.: 2298

Bravo AF: 0.105

Asia WGS AF: 0.179 AC: 620 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.1
DANN	Benign	0.74
PhyloP100		0.098

Splicing

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

Other links and lift over

dbSNP: rs2835189; hg19: chr21-37342121;