chr6-45328881-T-C

Position:

• chr6-45328881-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001024630.4(RUNX2):​c.58+97T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,236,318 control chromosomes in the GnomAD database, including 50,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4603 hom., cov: 32)
  • Exomes 𝑓: 0.28 (45691 hom.)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.445

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 6-45328881-T-C is Benign according to our data. Variant chr6-45328881-T-C is described in ClinVar as [Benign]. Clinvar id is 1277725.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.58+97T>C		intron_variant		ENST00000647337.2	NP_001019801.3
SUPT3H	NM_003599.4	c.101+36320A>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.101+36320A>G		intron_variant		1	NM_003599.4	ENSP00000360514	P1
RUNX2	ENST00000647337.2	c.58+97T>C		intron_variant			NM_001024630.4	ENSP00000495497	P4

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34501 AN: 151798 Hom.: 4603 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.241

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.0266

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.233

GnomAD4 exome AF: 0.280 AC: 303280 AN: 1084400 Hom.: 45691 AF XY: 0.277 AC XY: 153968 AN XY: 556050

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.0223

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.260

GnomAD4 genome AF: 0.227 AC: 34515 AN: 151918 Hom.: 4603 Cov.: 32 AF XY: 0.225 AC XY: 16674 AN XY: 74250

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.0267

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.309

Gnomad4 OTH AF: 0.231

Alfa AF: 0.182 Hom.: 487

Bravo AF: 0.215

Asia WGS AF: 0.0950 AC: 332 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.55
DANN	Benign	0.70

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: rs12205523; hg19: chr6-45296618;