chr21-34787947-C-G

Position:

• chr21-34787947-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: This 3' UTR c.*4188G>C variant is located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP = -0.665764 in GRCh38). The variant is present in gnomAD at an allele frequency between 0.015% and 0.15% in a general continental population (European, non-Finnish, subpopulation: 0.03528% in v3) with >5 variant alleles and a minimum of 2000 total alleles (BS1) and has not been described in the literature. 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: BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10644605/MONDO:0011071/008

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: RUNX1 NM_001754.5 3_prime_UTR
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: -0.646

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 Likely_benign. Variant got -4 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX1	NM_001754.5	c.*4188G>C		3_prime_UTR_variant	9/9	ENST00000675419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX1	ENST00000675419.1	c.*4188G>C		3_prime_UTR_variant	9/9		NM_001754.5	A1
RUNX1	ENST00000300305.7	c.*4188G>C		3_prime_UTR_variant	8/8	1		A1
RUNX1	ENST00000344691.8	c.*4188G>C		3_prime_UTR_variant	6/6	1		P4
RUNX1	ENST00000437180.5	c.*4188G>C		3_prime_UTR_variant	9/9	5		A1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000958

GnomAD4 exome AF: 0.000383 AC: 31 AN: 81032 Hom.: 0 Cov.: 0 AF XY: 0.000402 AC XY: 15 AN XY: 37268

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000401

Gnomad4 ASJ exome AF: 0.000195

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000519

Gnomad4 OTH exome AF: 0.000443

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74502

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000948

Bravo AF: 0.000234

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary thrombocytopenia and hematologic cancer predisposition syndrome Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Myeloid Malignancy Variant Curation Expert Panel

May 26, 2021

This 3' UTR c.*4188G>C variant is located at a non-conserved nucleotide per an evolutionary conservation prediction algorithm (PhyloP = -0.665764 in GRCh38). The variant is present in gnomAD at an allele frequency between 0.015% and 0.15% in a general continental population (European, non-Finnish, subpopulation: 0.03528% in v3) with >5 variant alleles and a minimum of 2000 total alleles (BS1) and has not been described in the literature. 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: BS1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.12
DANN	Benign	0.69

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: rs761390141; hg19: chr21-36160244;