dbSNP rs3749863: RUNX2:c.59-45082A>C (chr6-45377511-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001024630.4(RUNX2):c.59-45082A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 151,704 control chromosomes in the GnomAD database, including 38,179 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.69 ( 38161 hom., cov: 29)

Exomes 𝑓: 0.63 ( 18 hom. )

Consequence

RUNX2
NM_001024630.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.486

Publications

14 publications found

Variant links:

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]

RUNX2 links:

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]

SUPT3H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4 link	c.59-45082A>C		intron_variant	Intron 2 of 8	ENST00000647337.2	NP_001019801.3	Q13950-1
SUPT3H	NM_003599.4 link	c.-1+257T>G		intron_variant	Intron 1 of 10	ENST00000371459.6	NP_003590.1	O75486-1A0A024RD67

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2 link	c.59-45082A>C		intron_variant	Intron 2 of 8		NM_001024630.4	ENSP00000495497.1		Q13950-1
SUPT3H	ENST00000371459.6 link	c.-1+257T>G		intron_variant	Intron 1 of 10	1	NM_003599.4	ENSP00000360514.1		O75486-1

Frequencies

GnomAD3 genomes

AF:

0.694

AC:

105115

AN:

151494

Hom.:

38104

Cov.:

show subpopulations

Gnomad AFR

AF:

0.916

Gnomad AMI

AF:

0.602

Gnomad AMR

AF:

0.701

Gnomad ASJ

AF:

0.600

Gnomad EAS

AF:

0.425

Gnomad SAS

AF:

0.604

Gnomad FIN

AF:

0.595

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.606

Gnomad OTH

AF:

0.667

GnomAD4 exome

AF:

0.633

AC:

AN:

Hom.:

AF XY:

0.667

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.750

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.625

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.639

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.694

AC:

105218

AN:

151614

Hom.:

38161

Cov.:

AF XY:

0.691

AC XY:

51182

AN XY:

74060

show subpopulations

African (AFR)

AF:

0.916

AC:

37882

AN:

41366

American (AMR)

AF:

0.700

AC:

10678

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.600

AC:

2081

AN:

3468

East Asian (EAS)

AF:

0.425

AC:

2160

AN:

5080

South Asian (SAS)

AF:

0.605

AC:

2899

AN:

4794

European-Finnish (FIN)

AF:

0.595

AC:

6255

AN:

10520

Middle Eastern (MID)

AF:

0.673

AC:

198

AN:

294

European-Non Finnish (NFE)

AF:

0.606

AC:

41128

AN:

67832

Other (OTH)

AF:

0.659

AC:

1390

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1482

2964

4445

5927

7409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

806

1612

2418

3224

4030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.632

Hom.:

46062

Bravo

AF:

0.713

Asia WGS

AF:

0.548

AC:

1905

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

0.49

PromoterAI

0.041

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over