chr6-45328715-AAAG-A

Position:

• chr6-45328715-AAAG-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001024630.4(RUNX2):​c.-11_-9del 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

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 579 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.-11_-9del		5_prime_UTR_variant	2/9	ENST00000647337.2	NP_001019801.3
SUPT3H	NM_003599.4	c.101+36483_101+36485del		intron_variant		ENST00000371459.6	NP_003590.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.-11_-9del		5_prime_UTR_variant	2/9		NM_001024630.4	ENSP00000495497	P4
SUPT3H	ENST00000371459.6	c.101+36483_101+36485del		intron_variant		1	NM_003599.4	ENSP00000360514	P1

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

GnomAD3 exomes AF: 0.00411 AC: 1022 AN: 248668 Hom.: 9 AF XY: 0.00407 AC XY: 549 AN XY: 134888

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 SAS exome AF: 0.00108

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

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.000494

Gnomad4 ASJ exome AF: 0.000691

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.0221

Gnomad4 NFE exome AF: 0.00411

Gnomad4 OTH exome AF: 0.00302

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

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.000657

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0228

Gnomad4 NFE AF: 0.00418

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00355 Hom.: 0

Bravo AF: 0.00211

EpiCase AF: 0.00426

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RUNX2: BS1 -

Cleidocranial dysostosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs139788537; hg19: chr6-45296452;