NM_021961.6:c.1261T>C

Variant names:

• chr11-12937202-T-C
• rs11567847
• NM_021961.6:c.1261T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_021961.6(TEAD1):​c.1261T>C​(p.Tyr421His) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y421N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TEAD1 NM_021961.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 35 publications found

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]

TEAD1 Gene-Disease associations (from GenCC):

• helicoid peripapillary chorioretinal degeneration

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Aicardi syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• 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-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 984436.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 11-12937202-T-C is Pathogenic according to our data. Variant chr11-12937202-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12630.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEAD1	NM_021961.6	c.1261T>C	p.Tyr421His	missense_variant	Exon 13 of 13	ENST00000527636.7	NP_068780.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEAD1	ENST00000527636.7	c.1261T>C	p.Tyr421His	missense_variant	Exon 13 of 13	1	NM_021961.6	ENSP00000435233.2
TEAD1	ENST00000334310.10	c.1054T>C	p.Tyr352His	missense_variant	Exon 12 of 12	1		ENSP00000334754.6
TEAD1	ENST00000526600.1	c.973T>C	p.Tyr325His	missense_variant	Exon 8 of 8	1		ENSP00000435393.1
TEAD1	ENST00000527575.6	c.1087T>C	p.Tyr363His	missense_variant	Exon 11 of 11	5		ENSP00000435977.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000789 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Helicoid peripapillary chorioretinal degeneration Pathogenic:1

Oct 05, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	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	0.44	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.9	.;.;.;M;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.5	D;D;D;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;.;D
Polyphen		1.0	.;.;.;D;D
Vest4		0.85, 0.91
MutPred		0.65		Gain of disorder (P = 0.0121);.;.;Gain of disorder (P = 0.0121);.;
MVP		0.86
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.78
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs11567847; hg19: chr11-12958749;