6-45328740-G-A

Variant names:

• chr6-45328740-G-A
• rs541256105
• NM_001024630.4:c.14G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001024630.4(RUNX2):​c.14G>A​(p.Ser5Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,002 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S5T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.36
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.6033 (below the threshold of 3.09). Trascript score misZ: 1.7818 (below the threshold of 3.09). GenCC associations: The gene is linked to cleidocranial dysplasia 1, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome.

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.14G>A	p.Ser5Asn	missense	Exon 2 of 9	NP_001019801.3	Q13950-1
	SUPT3H	NM_003599.4	MANE Select	c.101+36461C>T		intron	N/A	NP_003590.1	O75486-1
	RUNX2	NM_001015051.4		c.14G>A	p.Ser5Asn	missense	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.14G>A	p.Ser5Asn	missense	Exon 2 of 9	ENSP00000495497.1	Q13950-1
	SUPT3H	ENST00000371459.6	TSL:1 MANE Select	c.101+36461C>T		intron	N/A	ENSP00000360514.1	O75486-1
	SUPT3H	ENST00000371460.5	TSL:1	c.-51-5773C>T		intron	N/A	ENSP00000360515.1	O75486-4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248590 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41512

American (AMR) AF: 0.0000658 AC: 1 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67940

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.90	L
PhyloP100		9.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.70
MVP		0.87
MPC		1.3
ClinPred		0.72	D
GERP RS		5.6
PromoterAI		-0.0068	Neutral
Varity_R		0.59
gMVP		0.69
Mutation Taster		=35/65	disease causing

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: rs541256105; hg19: chr6-45296477;