12-2994854-G-C

Variant names:

• chr12-2994854-G-C
• rs200185504
• NM_003213.4:c.88G>C

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.88G>C​(p.Ala30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. A30S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TEAD4 NM_003213.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.34
• 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=0.23048654).

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.88G>C	p.Ala30Pro	missense	Exon 3 of 13	NP_003204.2
	TEAD4	NM_201441.3		c.88G>C	p.Ala30Pro	missense	Exon 3 of 12	NP_958849.1	Q15561-3
	TEAD4	NM_201443.3		c.-161-16150G>C		intron	N/A	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.88G>C	p.Ala30Pro	missense	Exon 3 of 13	ENSP00000352926.3	Q15561-1
	TEAD4	ENST00000358409.7	TSL:1	c.88G>C	p.Ala30Pro	missense	Exon 3 of 12	ENSP00000351184.3	Q15561-3
	TEAD4	ENST00000397122.6	TSL:1	c.-161-16150G>C		intron	N/A	ENSP00000380311.2	Q15561-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.045
Sift	Benign	0.17	T
Sift4G	Uncertain	0.025	D
MVP		0.35
ClinPred		0.88	D
GERP RS		3.5
gMVP		0.61
Mutation Taster		=100/0	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: rs200185504; hg19: chr12-3104020;