chr6-35476383-C-A

Position:

• chr6-35476383-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003214.4(TEAD3):​c.645G>T​(p.Trp215Cys) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: TEAD3 NM_003214.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

Genes affected

TEAD3 (HGNC:11716): (TEA domain transcription factor 3) 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 predominantly expressed in the placenta and is involved in the transactivation of the chorionic somatomammotropin-B gene enhancer. Translation of this protein is initiated at a non-AUG (AUA) start codon. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TEAD3	NM_003214.4	c.645G>T	p.Trp215Cys	missense_variant	9/13	ENST00000338863.13	NP_003205.2
TEAD3	NM_001395214.1	c.645G>T	p.Trp215Cys	missense_variant	9/13		NP_001382143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TEAD3	ENST00000338863.13	c.645G>T	p.Trp215Cys	missense_variant	9/13	1	NM_003214.4	ENSP00000345772.8
TEAD3	ENST00000639578.3	c.645G>T	p.Trp215Cys	missense_variant	9/13	1		ENSP00000492431.3
TEAD3	ENST00000402886.9	n.*46G>T		non_coding_transcript_exon_variant	7/11	1		ENSP00000384577.5
TEAD3	ENST00000402886.9	n.*46G>T		3_prime_UTR_variant	7/11	1		ENSP00000384577.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.645G>T (p.W215C) alteration is located in exon 9 (coding exon 8) of the TEAD3 gene. This alteration results from a G to T substitution at nucleotide position 645, causing the tryptophan (W) at amino acid position 215 to be replaced by a cysteine (C). 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	0.94
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;.
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	-0.27	T
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-11	D;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0040	D;.
MutPred		0.81		Gain of disorder (P = 0.0382);Gain of disorder (P = 0.0382);
MVP		0.45
ClinPred		1.0	D
GERP RS		4.8
gMVP		0.79

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: chr6-35444160;