rs16873379

Positions:

• chr6-45372114-T-C

Variant summary

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

The NM_001024630.4(RUNX2):​c.58+43330T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 694,038 control chromosomes in the GnomAD database, including 5,670 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 0.13 (1585 hom., cov: 32)
  • Exomes 𝑓: 0.12 (4085 hom.)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.525

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=-0.63).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.58+43330T>C		intron_variant		ENST00000647337.2	NP_001019801.3
SUPT3H	NM_003599.4	c.-1+5654A>G		intron_variant		ENST00000371459.6	NP_003590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUPT3H	ENST00000371459.6	c.-1+5654A>G		intron_variant		1	NM_003599.4	ENSP00000360514	P1
RUNX2	ENST00000647337.2	c.58+43330T>C		intron_variant			NM_001024630.4	ENSP00000495497	P4

Frequencies

GnomAD3 genomes AF: 0.134 AC: 20372 AN: 152128 Hom.: 1581 Cov.: 32

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.122 AC: 66124 AN: 541792 Hom.: 4085 AF XY: 0.121 AC XY: 30827 AN XY: 254334

Gnomad4 AFR exome AF: 0.0933

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.153

Gnomad4 EAS exome AF: 0.244

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.0815

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.136

GnomAD4 genome AF: 0.134 AC: 20391 AN: 152246 Hom.: 1585 Cov.: 32 AF XY: 0.138 AC XY: 10257 AN XY: 74442

Gnomad4 AFR AF: 0.0977

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.259

Gnomad4 SAS AF: 0.133

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.143

Alfa AF: 0.129 Hom.: 207

Bravo AF: 0.143

Asia WGS AF: 0.186 AC: 644 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.3
DANN	Benign	0.90

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: rs16873379; hg19: chr6-45339851;