chr6-35476004-T-C

Position:

• chr6-35476004-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003214.4(TEAD3):​c.815A>G​(p.Tyr272Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000424 in 1,414,230 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: TEAD3 NM_003214.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TEAD3	NM_003214.4	c.815A>G	p.Tyr272Cys	missense_variant	10/13	ENST00000338863.13	NP_003205.2
TEAD3	NM_001395214.1	c.815A>G	p.Tyr272Cys	missense_variant	10/13		NP_001382143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TEAD3	ENST00000338863.13	c.815A>G	p.Tyr272Cys	missense_variant	10/13	1	NM_003214.4	ENSP00000345772.8
TEAD3	ENST00000639578.3	c.815A>G	p.Tyr272Cys	missense_variant	10/13	1		ENSP00000492431.3
TEAD3	ENST00000402886.9	n.*216A>G		non_coding_transcript_exon_variant	8/11	1		ENSP00000384577.5
TEAD3	ENST00000402886.9	n.*216A>G		3_prime_UTR_variant	8/11	1		ENSP00000384577.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000424 AC: 6 AN: 1414230 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 699902

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000550

Gnomad4 OTH exome AF: 0.00

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

Dec 21, 2023

The c.815A>G (p.Y272C) alteration is located in exon 10 (coding exon 9) of the TEAD3 gene. This alteration results from a A to G substitution at nucleotide position 815, causing the tyrosine (Y) at amino acid position 272 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	Benign	0.25
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;.
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.33	T
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.0	D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.017	D;.
MutPred		0.69		Loss of phosphorylation at Y272 (P = 0.0284);Loss of phosphorylation at Y272 (P = 0.0284);
MVP		0.56
ClinPred		1.0	D
GERP RS		5.6
gMVP		0.59

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: chr6-35443781;