12-3012178-C-G

Variant names:

• chr12-3012178-C-G
• NM_003213.4:c.300C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003213.4(TEAD4):​c.300C>G​(p.Ser100Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TEAD4 NM_003213.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.706
• Publications: 0 publications found

Genes affected

TEAD4 (HGNC:11717): (TEA domain transcription factor 4) This gene product is a member of the transcriptional enhancer factor (TEF) family of transcription factors, which contain the TEA/ATTS DNA-binding domain. It is preferentially expressed in the skeletal muscle, and binds to the M-CAT regulatory element found in promoters of muscle-specific genes to direct their gene expression. Alternatively spliced transcripts encoding distinct isoforms, some of which are translated through the use of a non-AUG (UUG) initiation codon, have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003213.4. 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
	TEAD4	NM_003213.4	MANE Select	c.300C>G	p.Ser100Arg	missense	Exon 5 of 13	NP_003204.2
	TEAD4	NM_201441.3		c.300C>G	p.Ser100Arg	missense	Exon 5 of 12	NP_958849.1	Q15561-3
	TEAD4	NM_201443.3		c.-88C>G		5_prime_UTR	Exon 3 of 11	NP_958851.1	Q15561-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEAD4	ENST00000359864.8	TSL:1 MANE Select	c.300C>G	p.Ser100Arg	missense	Exon 5 of 13	ENSP00000352926.3	Q15561-1
	TEAD4	ENST00000358409.7	TSL:1	c.300C>G	p.Ser100Arg	missense	Exon 5 of 12	ENSP00000351184.3	Q15561-3
	TEAD4	ENST00000397122.6	TSL:1	c.-88C>G		5_prime_UTR	Exon 3 of 11	ENSP00000380311.2	Q15561-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.31	T
PhyloP100		0.71
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.013	D
MutPred		0.77		Loss of phosphorylation at S100 (P = 0.0541)
MVP		0.49
ClinPred		1.0	D
GERP RS		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.88
Mutation Taster		=297/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr12-3121344;