Starting

Initialising…

RUNX1

Final classification

VUS

RUNX1 c.569G>A · p.Gly190Glu

RUNX1

The RUNX1 c.569G>A (p.Gly190Glu) variant has been reported in ClinVar, including an expert-panel assertion of uncertain significance.

Gene

RUNX1

Transcript

NM_001001890.2

HGVS · transcript:coding

NM_001001890.2:c.569G>A

Consequence

N/A

GRCh38

chr21:34834565 C>T

GRCh37

chr21:36206862 C>T

Basis Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM1 supporting (+1) + PM2 supporting (+1) = 2 points, which maps to VUS. ▾

Tavtigian et.al., 2020 - Bayesian adaptation of Richards et.al., 2015 v3.1.0 point-based framework: PM1 supporting (+1) + PM2 supporting (+1) = 2 points, which maps to VUS.

Classification rationale

PM1PM2 VUS

RUNX1 c.569G>A

The RUNX1 c.569G>A (p.Gly190Glu) variant has been reported in ClinVar, including an expert-panel assertion of uncertain significance.¹ This variant is absent from gnomAD v4.1 and is present only once in gnomAD v2.1 (1/250682 alleles; AF 3.98912e-06, 0.00040%), which supports rarity under the RUNX1 PM2_Supporting threshold of 0.00005.² The altered residue lies within the RUNX1 Runt homology domain residue range 89-204, supporting PM1 at supporting strength, but it is not one of the codons specified for PM1_Strong.³ Computational evidence is mixed but does not meet RUNX1 VCEP thresholds for either PP3 or BP4: REVEL is 0.666, BayesDel is 0.313044, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.⁴

PM1 + PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗

4 revelbayesdelspliceai ↗cspec ↗

Gene diagram · NM_001001890.2 · variants mapped to exon structure

RUNX1 NM_001001890.2

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.98912e-06; MAF= 0.00040%, 1/250682 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83174e-06; MAF= 0.00088%, 1/113228 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

0.0004% · 1 / 250,682
0 hom

European (non-Finnish)

1 / 113,228

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Uncertain Significance by ClinGen Myeloid Malignancy Variant Curation Expert Panel (expert panel). (ClinVarID = 3791471)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.666. BayesDel score = 0.313044.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RUNX1, a transcription factor involved in hematopoietic differentiation, is altered by mutation or chromosomal rearrangement in various hematologic ma

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 12 PMIDs not cited in assessment

23619275 ↗ ACMG position statement on prenatal/preconception expanded carrier screening. CLINVAR

23652378 ↗ A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document. CLINVAR

25626707 ↗ Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes. CLINVAR

25730230 ↗ Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. CLINVAR

23169492 ↗ The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes. CLINVAR

24121147 ↗ Appropriateness of newborn screening for α1-antitrypsin deficiency. CLINVAR

22947299 ↗ Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening. CLINVAR

23037933 ↗ Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children. CLINVAR

23881473 ↗ Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors. CLINVAR

24022298 ↗ Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected]. CLINVAR

24394680 ↗ Parental permission for pilot newborn screening research: guidelines from the NBSTRN. CLINVAR

31022120 ↗ ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist. CLINVAR