6-45348008-T-C

Variant names:

• chr6-45348008-T-C
• rs9472464
• NM_001024630.4:c.58+19224T>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+19224T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 152,020 control chromosomes in the GnomAD database, including 2,147 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 0.15 (2147 hom., cov: 31)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.889
• Publications: 1 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.58+19224T>C		intron_variant	Intron 2 of 8	ENST00000647337.2	NP_001019801.3
SUPT3H	NM_003599.4	c.101+17193A>G		intron_variant	Intron 2 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+19224T>C		intron_variant	Intron 2 of 8		NM_001024630.4	ENSP00000495497.1
SUPT3H	ENST00000371459.6	c.101+17193A>G		intron_variant	Intron 2 of 10	1	NM_003599.4	ENSP00000360514.1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22163 AN: 151902 Hom.: 2140 Cov.: 31

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.0972

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0762

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.0934

Gnomad OTH AF: 0.140

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.146 AC: 22198 AN: 152020 Hom.: 2147 Cov.: 31 AF XY: 0.145 AC XY: 10805 AN XY: 74348

African (AFR) AF: 0.271 AC: 11253 AN: 41452

American (AMR) AF: 0.152 AC: 2322 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0972 AC: 337 AN: 3466

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5176

South Asian (SAS) AF: 0.0775 AC: 374 AN: 4826

European-Finnish (FIN) AF: 0.106 AC: 1116 AN: 10560

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.0934 AC: 6349 AN: 67948

Other (OTH) AF: 0.138 AC: 291 AN: 2110

Alfa AF: 0.108 Hom.: 829

Bravo AF: 0.155

Asia WGS AF: 0.0570 AC: 200 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.4
DANN	Benign	0.63
PhyloP100		-0.89
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: rs9472464; hg19: chr6-45315745;