rs11567847

Positions:

• chr11-12937202-T-A
• chr11-12937202-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_021961.6(TEAD1):​c.1261T>A​(p.Tyr421Asn) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y421H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TEAD1 NM_021961.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 8.02

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 8 ACMG points.

• PM1: In a strand (size 7) in uniprot entity TEAD1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_021961.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-12937202-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TEAD1	NM_021961.6	c.1261T>A	p.Tyr421Asn	missense_variant	13/13	ENST00000527636.7	NP_068780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TEAD1	ENST00000527636.7	c.1261T>A	p.Tyr421Asn	missense_variant	13/13	1	NM_021961.6	ENSP00000435233
TEAD1	ENST00000334310.10	c.1054T>A	p.Tyr352Asn	missense_variant	12/12	1		ENSP00000334754	P1
TEAD1	ENST00000526600.1	c.973T>A	p.Tyr325Asn	missense_variant	8/8	1		ENSP00000435393
TEAD1	ENST00000527575.6	c.1087T>A	p.Tyr363Asn	missense_variant	11/11	5		ENSP00000435977

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Helicoid peripapillary chorioretinal degeneration Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory for Molecular Genetic Diagnostic of Neurological Diseases, University of Belgrade, School of Medicine	Nov 10, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 11, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;D;.;D;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.9	.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.2	D;D;D;.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;.;D
Polyphen		1.0	.;.;.;D;D
Vest4		0.92, 0.95
MutPred		0.59		Loss of sheet (P = 0.007);.;.;Loss of sheet (P = 0.007);.;
MVP		0.93
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.90
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs11567847; hg19: chr11-12958749;