chr6-45328602-A-G

Variant names:

• chr6-45328602-A-G
• rs145364349
• NM_001024630.4:c.-66-59A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001024630.4(RUNX2):​c.-66-59A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,604,222 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (8 hom., cov: 32)
  • Exomes 𝑓: 0.010 (107 hom.)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.37
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-45328602-A-G is Benign according to our data. Variant chr6-45328602-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1196317.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00754 (1147/152152) while in subpopulation NFE AF = 0.0126 (859/67968). AF 95% confidence interval is 0.0119. There are 8 homozygotes in GnomAd4. There are 552 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1147 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.-66-59A>G		intron_variant	Intron 1 of 8	ENST00000647337.2	NP_001019801.3
SUPT3H	NM_003599.4	c.101+36599T>C		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.-66-59A>G		intron_variant	Intron 1 of 8		NM_001024630.4	ENSP00000495497.1
SUPT3H	ENST00000371459.6	c.101+36599T>C		intron_variant	Intron 2 of 10	1	NM_003599.4	ENSP00000360514.1

Frequencies

GnomAD3 genomes AF: 0.00755 AC: 1148 AN: 152034 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00980

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0101

GnomAD4 exome AF: 0.0104 AC: 15134 AN: 1452070 Hom.: 107 Cov.: 31 AF XY: 0.0101 AC XY: 7333 AN XY: 722590

African (AFR) AF: 0.00176 AC: 58 AN: 32864

American (AMR) AF: 0.00322 AC: 141 AN: 43780

Ashkenazi Jewish (ASJ) AF: 0.00156 AC: 40 AN: 25626

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.000258 AC: 22 AN: 85322

European-Finnish (FIN) AF: 0.00904 AC: 480 AN: 53114

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5660

European-Non Finnish (NFE) AF: 0.0125 AC: 13830 AN: 1106636

Other (OTH) AF: 0.00941 AC: 562 AN: 59724

GnomAD4 genome AF: 0.00754 AC: 1147 AN: 152152 Hom.: 8 Cov.: 32 AF XY: 0.00742 AC XY: 552 AN XY: 74392

African (AFR) AF: 0.00219 AC: 91 AN: 41536

American (AMR) AF: 0.00420 AC: 64 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00980 AC: 104 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 859 AN: 67968

Other (OTH) AF: 0.00996 AC: 21 AN: 2108

Alfa AF: 0.0100 Hom.: 1

Bravo AF: 0.00668

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.89
PhyloP100		3.4
PromoterAI		-0.0054	Neutral
Mutation Taster		=100/0	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: rs145364349; hg19: chr6-45296339;