rs3749863

chr6-45377511-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001024630.4(RUNX2):c.59-45082A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 151,704 control chromosomes in the GnomAD database, including 38,179 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (38161 hom., cov: 29)
  • Exomes 𝑓: 0.63 (18 hom.)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.486

Genes affected

RUNX2 (HGNC:10472): (RUNX family transcription factor 2) This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Two regions of potential trinucleotide repeat expansions are present in the N-terminal region of the encoded protein, and these and other mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing. [provided by RefSeq, Jul 2016]

SUPT3H (HGNC:11466): (SPT3 homolog, SAGA and STAGA complex component) Enables transcription coactivator activity. Involved in histone H3 acetylation and histone deubiquitination. Located in nucleoplasm. Part of SAGA complex and transcription factor TFTC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX2	NM_001024630.4	c.59-45082A>C		intron_variant		ENST00000647337.2
SUPT3H	NM_003599.4	c.-1+257T>G		intron_variant		ENST00000371459.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUPT3H	ENST00000371459.6	c.-1+257T>G		intron_variant		1	NM_003599.4	P1
RUNX2	ENST00000647337.2	c.59-45082A>C		intron_variant			NM_001024630.4	P4

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105115 AN: 151494 Hom.: 38104 Cov.: 29

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.600

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.667

GnomAD4 exome AF: 0.633 AC: 57 AN: 90 Hom.: 18 AF XY: 0.667 AC XY: 48 AN XY: 72

Gnomad4 AFR exome AF: 1.00

Gnomad4 EAS exome AF: 0.750

Gnomad4 FIN exome AF: 0.625

Gnomad4 NFE exome AF: 0.639

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.694 AC: 105218 AN: 151614 Hom.: 38161 Cov.: 29 AF XY: 0.691 AC XY: 51182 AN XY: 74060

Gnomad4 AFR AF: 0.916

Gnomad4 AMR AF: 0.700

Gnomad4 ASJ AF: 0.600

Gnomad4 EAS AF: 0.425

Gnomad4 SAS AF: 0.605

Gnomad4 FIN AF: 0.595

Gnomad4 NFE AF: 0.606

Gnomad4 OTH AF: 0.659

Alfa AF: 0.659 Hom.: 4523

Bravo AF: 0.713

Asia WGS AF: 0.548 AC: 1905 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	15
Dann	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3749863; hg19: chr6-45345248;