chr6-45328715-AAAG-A

Variant names:

• chr6-45328715-AAAG-A
• rs139788537
• NM_001024630.4:c.-11_-9delAAG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001024630.4(RUNX2):​c.-11_-9delAAG variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00415 in 1,612,112 control chromosomes in the GnomAD database, including 36 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (30 hom.)
• Consequence: RUNX2 NM_001024630.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.37
• 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 -16 ACMG points.

• BP6: Variant 6-45328715-AAAG-A is Benign according to our data. Variant chr6-45328715-AAAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 357089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00381 (579/152112) while in subpopulation NFE AF = 0.00418 (284/67948). AF 95% confidence interval is 0.00378. There are 6 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 579 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.-11_-9delAAG		5_prime_UTR	Exon 2 of 9	NP_001019801.3	Q13950-1
	SUPT3H	NM_003599.4	MANE Select	c.101+36483_101+36485delCTT		intron	N/A	NP_003590.1	O75486-1
	RUNX2	NM_001015051.4		c.-11_-9delAAG		5_prime_UTR	Exon 2 of 8	NP_001015051.3	Q13950-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.-11_-9delAAG		5_prime_UTR	Exon 2 of 9	ENSP00000495497.1	Q13950-1
	SUPT3H	ENST00000371459.6	TSL:1 MANE Select	c.101+36483_101+36485delCTT		intron	N/A	ENSP00000360514.1	O75486-1
	SUPT3H	ENST00000371460.5	TSL:1	c.-51-5751_-51-5749delCTT		intron	N/A	ENSP00000360515.1	O75486-4

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 580 AN: 151994 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000658

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00411 AC: 1022 AN: 248668 AF XY: 0.00407

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0230

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00419 AC: 6112 AN: 1460000 Hom.: 30 AF XY: 0.00407 AC XY: 2954 AN XY: 726314

African (AFR) AF: 0.000360 AC: 12 AN: 33378

American (AMR) AF: 0.000494 AC: 22 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.000691 AC: 18 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00143 AC: 123 AN: 86236

European-Finnish (FIN) AF: 0.0221 AC: 1182 AN: 53412

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5754

European-Non Finnish (NFE) AF: 0.00411 AC: 4570 AN: 1110702

Other (OTH) AF: 0.00302 AC: 182 AN: 60276

GnomAD4 genome AF: 0.00381 AC: 579 AN: 152112 Hom.: 6 Cov.: 32 AF XY: 0.00489 AC XY: 364 AN XY: 74376

African (AFR) AF: 0.000554 AC: 23 AN: 41552

American (AMR) AF: 0.000657 AC: 10 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3464

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5158

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00418 AC: 284 AN: 67948

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00355 Hom.: 0

Bravo AF: 0.00211

EpiCase AF: 0.00426

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cleidocranial dysostosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.4
Mutation Taster		=195/5	polymorphism

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: rs139788537; hg19: chr6-45296452;