chr12-3017510-G-T

Variant names:

• chr12-3017510-G-T
• rs139665156
• NM_003213.4:c.467G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003213.4(TEAD4):​c.467G>T​(p.Arg156Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 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. R156H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TEAD4 NM_003213.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.280
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07168126).

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.467G>T	p.Arg156Leu	missense	Exon 6 of 13	NP_003204.2
	TEAD4	NM_201443.3		c.80G>T	p.Arg27Leu	missense	Exon 4 of 11	NP_958851.1	Q15561-2
	TEAD4	NM_201441.3		c.355-1035G>T		intron	N/A	NP_958849.1	Q15561-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEAD4	ENST00000359864.8	TSL:1 MANE Select	c.467G>T	p.Arg156Leu	missense	Exon 6 of 13	ENSP00000352926.3	Q15561-1
	TEAD4	ENST00000397122.6	TSL:1	c.80G>T	p.Arg27Leu	missense	Exon 4 of 11	ENSP00000380311.2	Q15561-2
	TEAD4	ENST00000358409.7	TSL:1	c.355-1035G>T		intron	N/A	ENSP00000351184.3	Q15561-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461152 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726860

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111798

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.28
PrimateAI	Benign	0.19	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.073
Sift	Benign	0.67	T
Sift4G	Benign	0.66	T
Vest4		0.16
MutPred		0.41		Gain of catalytic residue at R156 (P = 0.0011)
MVP		0.34
ClinPred		0.13	T
GERP RS		2.1
gMVP		0.25
Mutation Taster		=93/7	polymorphism

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: rs139665156; hg19: chr12-3126676; COSMIC: COSV100622159;