21-34787897-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001754.5(RUNX1):c.*4238G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 233,384 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (0 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 0.303

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-34787897-C-A is Benign according to our data. Variant chr21-34787897-C-A is described in ClinVar as [Benign]. Clinvar id is 339793.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00343 (523/152370) while in subpopulation NFE AF= 0.00489 (333/68036). AF 95% confidence interval is 0.00446. There are 2 homozygotes in gnomad4. There are 235 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 524 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.*4238G>T		3_prime_UTR_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.*4238G>T		3_prime_UTR_variant	9/9		NM_001754.5	A1
RUNX1	ENST00000300305.7	c.*4238G>T		3_prime_UTR_variant	8/8	1		A1
RUNX1	ENST00000344691.8	c.*4238G>T		3_prime_UTR_variant	6/6	1		P4
RUNX1	ENST00000437180.5	c.*4238G>T		3_prime_UTR_variant	9/9	5		A1

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 524 AN: 152252 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00405

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00513 AC: 416 AN: 81014 Hom.: 0 Cov.: 0 AF XY: 0.00559 AC XY: 208 AN XY: 37238

Gnomad4 AFR exome AF: 0.000513

Gnomad4 AMR exome AF: 0.00240

Gnomad4 ASJ exome AF: 0.0176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00285

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00567

Gnomad4 OTH exome AF: 0.00443

GnomAD4 genome AF: 0.00343 AC: 523 AN: 152370 Hom.: 2 Cov.: 32 AF XY: 0.00315 AC XY: 235 AN XY: 74508

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00489

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00391 Hom.: 0

Bravo AF: 0.00382

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

May 13, 2020

The c.*4238G>T variant in the 3' UTR has an MAF of 0.004815 (0.48%, 311/64584 alleles) in the non-Finish European subpopulation of the gnomAD v3 cohort and is >= 0.0015 (0.15%) (BA1). This variant is detected in a homozygous state in 1 individual in the gnomAD v2.1.1 population database (BP2). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BA1, BP2. -

Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.4
Dann	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs138870671; hg19: chr21-36160194;