12-3012178-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEAD4	NM_003213.4	c.300C>G	p.Ser100Arg	missense_variant	Exon 5 of 13	ENST00000359864.8	NP_003204.2
TEAD4	NM_201441.3	c.300C>G	p.Ser100Arg	missense_variant	Exon 5 of 12		NP_958849.1
TEAD4	NM_201443.3	c.-88C>G		5_prime_UTR_variant	Exon 3 of 11		NP_958851.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEAD4	ENST00000359864.8	c.300C>G	p.Ser100Arg	missense_variant	Exon 5 of 13	1	NM_003213.4	ENSP00000352926.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.300C>G (p.S100R) alteration is located in exon 5 (coding exon 3) of the TEAD4 gene. This alteration results from a C to G substitution at nucleotide position 300, causing the serine (S) at amino acid position 100 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.31	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.013	D;D;D
MutPred		0.77		Loss of phosphorylation at S100 (P = 0.0541);Loss of phosphorylation at S100 (P = 0.0541);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-3121344;