rs1157495777

Variant names:

• chr21-34886975-G-A
• rs1157495777
• NM_001754.5:c.219C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34886975-G-A
• chr21-34886975-G-C
• chr21-34886975-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP7 BP4

This summary comes from the ClinGen Evidence Repository: This synonymous variant is predicted by SSF and MES to lead to either an increase in the canonical splice site score or a decrease of the canonical splice site score by no more than 10% and no putative cryptic splice sites are created; in addition, evolutionary conservation prediction algorithms predict the site as not being highly conserved (PhyloP score 0.04 < 0.1[-14.1;6.4]) (BP4+BP7). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4 and BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA512318910/MONDO:0011071/008

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RUNX1 NM_001754.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:3
• Conservation: PhyloP100: 1.37
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.219C>T	p.Ser73Ser	synonymous	Exon 4 of 9	NP_001745.2
	RUNX1	NM_001001890.3		c.138C>T	p.Ser46Ser	synonymous	Exon 1 of 6	NP_001001890.1
	RUNX1	NM_001122607.2		c.138C>T	p.Ser46Ser	synonymous	Exon 1 of 5	NP_001116079.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.219C>T	p.Ser73Ser	synonymous	Exon 4 of 9	ENSP00000501943.1
	RUNX1	ENST00000300305.7	TSL:1	c.219C>T	p.Ser73Ser	synonymous	Exon 3 of 8	ENSP00000300305.3
	RUNX1	ENST00000344691.8	TSL:1	c.138C>T	p.Ser46Ser	synonymous	Exon 1 of 6	ENSP00000340690.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 239124 AF XY: 0.00000765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457112 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 724980

African (AFR) AF: 0.00 AC: 0 AN: 33420

American (AMR) AF: 0.0000225 AC: 1 AN: 44496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110980

Other (OTH) AF: 0.00 AC: 0 AN: 60264

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary thrombocytopenia and hematologic cancer predisposition syndrome (1)
-	-	1	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		1.4
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1157495777; hg19: chr21-36259272;