12-3012215-A-G

Variant names:

• chr12-3012215-A-G
• NM_003213.4:c.337A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003213.4(TEAD4):​c.337A>G​(p.Ile113Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TEAD4 NM_003213.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.40

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEAD4	NM_003213.4	c.337A>G	p.Ile113Val	missense_variant	Exon 5 of 13	ENST00000359864.8	NP_003204.2
TEAD4	NM_201441.3	c.337A>G	p.Ile113Val	missense_variant	Exon 5 of 12		NP_958849.1
TEAD4	NM_201443.3	c.-51A>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.337A>G	p.Ile113Val	missense_variant	Exon 5 of 13	1	NM_003213.4	ENSP00000352926.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337A>G (p.I113V) alteration is located in exon 5 (coding exon 3) of the TEAD4 gene. This alteration results from a A to G substitution at nucleotide position 337, causing the isoleucine (I) at amino acid position 113 to be replaced by a valine (V). 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	Benign	0.19
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.79	T
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.21	T;T;D
Sift4G	Benign	0.10	T;T;T
MutPred		0.54		Loss of catalytic residue at I113 (P = 0.2786);Loss of catalytic residue at I113 (P = 0.2786);Loss of catalytic residue at I113 (P = 0.2786);
MVP		0.39
ClinPred		0.96	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.44

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-3121381;