6-45338734-C-T

Variant names:

• chr6-45338734-C-T
• rs967588
• NM_001024630.4:c.58+9950C>T

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+9950C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 152,016 control chromosomes in the GnomAD database, including 2,034 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 (2034 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.09
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.58+9950C>T		intron_variant	Intron 2 of 8	ENST00000647337.2	NP_001019801.3
SUPT3H	NM_003599.4	c.101+26467G>A		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+9950C>T		intron_variant	Intron 2 of 8		NM_001024630.4	ENSP00000495497.1
SUPT3H	ENST00000371459.6	c.101+26467G>A		intron_variant	Intron 2 of 10	1	NM_003599.4	ENSP00000360514.1

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23329 AN: 151896 Hom.: 2033 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.249

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.161

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

GnomAD4 genome AF: 0.154 AC: 23344 AN: 152016 Hom.: 2034 Cov.: 32 AF XY: 0.159 AC XY: 11787 AN XY: 74316

African (AFR) AF: 0.117 AC: 4862 AN: 41470

American (AMR) AF: 0.249 AC: 3797 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 595 AN: 3470

East Asian (EAS) AF: 0.261 AC: 1350 AN: 5164

South Asian (SAS) AF: 0.220 AC: 1058 AN: 4816

European-Finnish (FIN) AF: 0.148 AC: 1565 AN: 10574

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9665 AN: 67962

Other (OTH) AF: 0.158 AC: 334 AN: 2108

Alfa AF: 0.147 Hom.: 264

Bravo AF: 0.160

Asia WGS AF: 0.241 AC: 834 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.32
DANN	Benign	0.40
PhyloP100		-2.1
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: rs967588; hg19: chr6-45306471;