rs16873379

Variant names:

• chr6-45372114-T-C
• rs16873379
• NM_001024630.4:c.58+43330T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.58+43330T>C		intron_variant	Intron 2 of 8	ENST00000647337.2	NP_001019801.3
SUPT3H	NM_003599.4	c.-1+5654A>G		intron_variant	Intron 1 of 10	ENST00000371459.6	NP_003590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.58+43330T>C		intron_variant	Intron 2 of 8		NM_001024630.4	ENSP00000495497.1
SUPT3H	ENST00000371459.6	c.-1+5654A>G		intron_variant	Intron 1 of 10	1	NM_003599.4	ENSP00000360514.1

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

African (AFR) AF: 0.0933 AC: 934 AN: 10014

American (AMR) AF: 0.252 AC: 156 AN: 620

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 513 AN: 3346

East Asian (EAS) AF: 0.244 AC: 567 AN: 2326

South Asian (SAS) AF: 0.144 AC: 1528 AN: 10594

European-Finnish (FIN) AF: 0.0815 AC: 15 AN: 184

Middle Eastern (MID) AF: 0.180 AC: 194 AN: 1078

European-Non Finnish (NFE) AF: 0.121 AC: 59862 AN: 496306

Other (OTH) AF: 0.136 AC: 2355 AN: 17324

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

African (AFR) AF: 0.0977 AC: 4058 AN: 41534

American (AMR) AF: 0.233 AC: 3559 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 583 AN: 3470

East Asian (EAS) AF: 0.259 AC: 1344 AN: 5192

South Asian (SAS) AF: 0.133 AC: 641 AN: 4822

European-Finnish (FIN) AF: 0.128 AC: 1362 AN: 10608

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8430 AN: 68016

Other (OTH) AF: 0.143 AC: 302 AN: 2110

Alfa AF: 0.128 Hom.: 213

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
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16873379; hg19: chr6-45339851;