21-34788555-A-C

Variant names:

• chr21-34788555-A-C
• rs373937576
• NM_001754.5:c.*3580T>G

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BS2BP4_StrongBP6_Very_Strong

The NM_001754.5(RUNX1):c.*3580T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000309 (AC=72) in the gnomAD database across 233,078 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00013. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (0 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:1
• Conservation: PhyloP100: 1.17
• 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: Orphanet, ClinGen
• hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

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

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

Classification according to ACMG Germline Pathogenicity v2019

Specifications for RUNX1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Benign. The variant received -16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar germline classification: Benign/Likely Benign, 3 star(s).
	BS2Observed in healthy adult		Pure AD gene with cumulative gnomAD AC ≥5 — observed in healthy adults (BS2); GnomAD homozygous count = 0.; Cumulative gnomAD AC = 72 (pure AD gene, not AR).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RUNX1 NM_001754.5	MANE Select	c.*3580T>G	3_prime_UTR	Exon 9 of 9	Prot: NP_001745.2
	RUNX1 NM_001001890.3		c.*3580T>G	3_prime_UTR	Exon 6 of 6	Prot: NP_001001890.1 UniProt:

RUNX1 NM_001754.5

MANE Select

HGVSc / HGVSpc.*3580T>G

Exon rankExon 9 of 9

3_prime_UTR

Prot: NP_001745.2

RUNX1 NM_001001890.3

HGVSc / HGVSpc.*3580T>G

Exon rankExon 6 of 6

3_prime_UTR

Prot: NP_001001890.1UniProt: Q01196-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RUNX1 ENST00000675419.1	MANE Select	c.*3580T>G	3_prime_UTR	Exon 9 of 9	Prot: ENSP00000501943.1 UniProt:
	RUNX1 ENST00000300305.7	TSL:1	c.*3580T>G	3_prime_UTR	Exon 8 of 8	Prot: ENSP00000300305.3 UniProt:
	RUNX1 ENST00000344691.8	TSL:1	c.*3580T>G	3_prime_UTR	Exon 6 of 6	Prot: ENSP00000340690.4 UniProt:

RUNX1 ENST00000675419.1

MANE Select

HGVSc / HGVSpc.*3580T>G

Exon rankExon 9 of 9

3_prime_UTR

Prot: ENSP00000501943.1UniProt: Q01196-8

RUNX1 ENST00000300305.7

TSL:1

HGVSc / HGVSpc.*3580T>G

Exon rankExon 8 of 8

3_prime_UTR

Prot: ENSP00000300305.3UniProt: Q01196-8

RUNX1 ENST00000344691.8

TSL:1

HGVSc / HGVSpc.*3580T>G

Exon rankExon 6 of 6

3_prime_UTR

Prot: ENSP00000340690.4UniProt: Q01196-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000223	AC:34	Hom:0	AN:152182	Cov:32
GnomAD4 exome	AF: 0.000470	AC:38	Hom:0	AN:80896	Cov:0
GnomAD4 genome	AF: 0.000223	AC:34	Hom:0	AN:152182	Cov:32
TOPMed (Bravo)	AF: 0.000325	AC:86	Hom:1	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000509	AC:1	Hom:0	AN:19644	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000223	AC:2	Hom:0	AN:8960	Cov:

Showing 6 sources

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (2)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	2.8
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.5
DANN	Benign	0.74
GPN-Star LLR	N/A	-0.36
GPN-Star score	N/A	0.36
PhyloP100	Benign	1.2
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	2.0

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs373937576;

hg19: chr21-36160852;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar