chr11-12764369-C-A

Position:

• chr11-12764369-C-A

Variant summary

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

The NM_021961.6(TEAD1):​c.137C>A​(p.Ala46Asp) 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. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TEAD1 NM_021961.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

TEAD1 (HGNC:11714): (TEA domain transcription factor 1) This gene encodes a ubiquitous transcriptional enhancer factor that is a member of the TEA/ATTS domain family. This protein directs the transactivation of a wide variety of genes and, in placental cells, also acts as a transcriptional repressor. Mutations in this gene cause Sveinsson's chorioretinal atrophy. Additional transcript variants have been described but their full-length natures have not been experimentally verified. [provided by RefSeq, May 2010]

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, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TEAD1	NM_021961.6	c.137C>A	p.Ala46Asp	missense_variant	3/13	ENST00000527636.7	NP_068780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TEAD1	ENST00000527636.7	c.137C>A	p.Ala46Asp	missense_variant	3/13	1	NM_021961.6	ENSP00000435233.2
TEAD1	ENST00000334310.10	c.92C>A	p.Ala31Asp	missense_variant	2/12	1		ENSP00000334754.6
TEAD1	ENST00000527575.6	c.137C>A	p.Ala46Asp	missense_variant	2/11	5		ENSP00000435977.2
TEAD1	ENST00000527376.3	c.137C>A	p.Ala46Asp	missense_variant	2/2	3		ENSP00000432587.4

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 provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 11, 2022

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with TEAD1-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 46 of the TEAD1 protein (p.Ala46Asp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D;.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.4	.;.;.;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.9	D;D;D;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	.;.;.;D
Vest4		0.97
MutPred		0.86		Gain of disorder (P = 0.0811);Gain of disorder (P = 0.0811);.;Gain of disorder (P = 0.0811);
MVP		0.76
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.99

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: chr11-12785916;