NM_001024630.4:c.-64T>C

Variant names:

• chr6-45328663-T-C
• rs750277342
• NM_001024630.4:c.-64T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001024630.4(RUNX2):​c.-64T>C variant causes a splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,459,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: RUNX2 NM_001024630.4 splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.48
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 6-45328663-T-C is Benign according to our data. Variant chr6-45328663-T-C is described in ClinVar as Benign. ClinVar VariationId is 357087.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024630.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	NM_001024630.4	MANE Select	c.-64T>C		splice_region	Exon 2 of 9	NP_001019801.3	Q13950-1
	RUNX2	NM_001024630.4	MANE Select	c.-64T>C		5_prime_UTR	Exon 2 of 9	NP_001019801.3	Q13950-1
	SUPT3H	NM_003599.4	MANE Select	c.101+36538A>G		intron	N/A	NP_003590.1	O75486-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.-64T>C		splice_region	Exon 2 of 9	ENSP00000495497.1	Q13950-1
	RUNX2	ENST00000647337.2	MANE Select	c.-64T>C		5_prime_UTR	Exon 2 of 9	ENSP00000495497.1	Q13950-1
	SUPT3H	ENST00000371459.6	TSL:1 MANE Select	c.101+36538A>G		intron	N/A	ENSP00000360514.1	O75486-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248752 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459284 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 725998

African (AFR) AF: 0.0000300 AC: 1 AN: 33342

American (AMR) AF: 0.0000224 AC: 1 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5742

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1110198

Other (OTH) AF: 0.0000332 AC: 2 AN: 60208

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cleidocranial dysostosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.91
PhyloP100		7.5
PromoterAI		0.0059	Neutral

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: rs750277342; hg19: chr6-45296400;