2-161423752-C-CGCTGCAG

Position:

• chr2-161423752-C-CGCTGCAG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006593.4(TBR1):​c.1588_1594dup​(p.Thr532ArgfsTer144) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBR1 NM_006593.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 O:1
• Conservation: PhyloP100: -1.77

Genes affected

TBR1 (HGNC:11590): (T-box brain transcription factor 1) This gene is a member of a conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of numerous developmental processes. In mouse, the ortholog of this gene is expressed in the cerebral cortex, hippocampus, amygdala and olfactory bulb and is thought to play an important role in neuronal migration and axonal projection. In mouse, the C-terminal region of this protein was found to be necessary and sufficient for association with the guanylate kinase domain of calcium/calmodulin-dependent serine protein kinase. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.232 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-161423752-C-CGCTGCAG is Pathogenic according to our data. Variant chr2-161423752-C-CGCTGCAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBR1	NM_006593.4	c.1588_1594dup	p.Thr532ArgfsTer144	frameshift_variant	6/6	ENST00000389554.8	NP_006584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBR1	ENST00000389554.8	c.1588_1594dup	p.Thr532ArgfsTer144	frameshift_variant	6/6	1	NM_006593.4	ENSP00000374205	P1
TBR1	ENST00000410035.1	c.727_733dup	p.Thr245ArgfsTer144	frameshift_variant	5/5	2		ENSP00000387023
TBR1	ENST00000411412.5	c.688_694dup	p.Thr232ArgfsTer?	frameshift_variant	6/6	5		ENSP00000393934
TBR1	ENST00000463544.1	n.7066_7072dup		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autism, susceptibility to, 5 Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 03, 2022	ACMG classification criteria: PVS1 strong, PS4 moderated, PM2 moderated, PM6 strong -
Pathogenic, no assertion criteria provided	clinical testing	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 07, 2019	- -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 22, 2021	Variant summary: TBR1 c.1588_1594dupGGCTGCA (p.Thr532ArgfsX144) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 104902 control chromosomes (gnomAD). c.1588_1594dupGGCTGCA has been reported in the literature as a de-novo occurrence in multiple individuals affected with intellectual disability (e.g. Gilissen_2014, Thevenon_2016, Bowling_2017, Vegas_2018, Bruel_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve ClinVar submissions (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=9), including eight reports of the variant as de-novo in origin. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2022	Frameshift variant predicted to result in protein truncation, as the last 151 amino acids are replaced with 143 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24896178, 30268909, 26757139, 28554332, 31231135, 32959227) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -

Intellectual developmental disorder with speech delay, autism, and dysmorphic facies Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 25, 2023

The p.Thr532ArgfsTer144 variant in TBR1 was identified by our study in one individual with global developmental delay and polymicrogyria. Trio exome analysis showed this variant to be de novo. The p.Thr532ArgfsTer144 variant in TBR1 has been previously reported in the literature in 7 unrelated individuals with intellectual developmental disorder with autism and speech delay (PMID: 32959227, PMID: 31231135, PMID: 26757139, PMID: 24896178, PMID: 30268909, PMID: 28554332). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in at least 7 individuals with confirmed paternity and maternity (PMID: 32959227, PMID: 30268909, PMID: 24896178, PMID: 26757139, PMID: 28554332, PMID: 31231135, SCV000599285.1, SCV000747915.2, SCV000747914.2, SCV001371835.1, SCV001371828.1, SCV000747913.2, SCV001149955.1, SCV000965704.1). This variant has also been reported in ClinVar (Variation ID: 224144) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 532 and leads to a premature termination codon 144 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the TBR1 gene is strongly associated to autosomal dominant intellectual developmental disorder with autism and speech delay. In summary, this variant meets criteria to be classified as pathogenic for intellectual developmental disorder with autism and speech delay. ACMG/AMP Criteria applied: PVS1_Supporting, PM2_Supporting, PS2_VeryStrong, PS4 (Richards 2015). -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2018

- -

Autistic behavior;C1837397:Severe global developmental delay;C4022749:Abnormal brainstem MRI signal intensity;C4023681:Delayed fine motor development Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jan 12, 2019

- -

Severe global developmental delay Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Oct 30, 2017

- -

Autistic behavior;C2237142:Moderate global developmental delay Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Mar 16, 2017

- -

Neurodevelopmental disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Feb 09, 2016

- -

Seizure;C0751837:Gait ataxia;C1837397:Severe global developmental delay;C2938983:Focal cortical dysplasia;C4023681:Delayed fine motor development Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Oct 15, 2018

- -

Autistic behavior Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Jan 01, 2014

- -

Gait ataxia;C1837397:Severe global developmental delay;C1849172:Hypoplasia of the frontal lobes;C4023681:Delayed fine motor development Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Feb 02, 2018

- -

Autistic behavior;C1837397:Severe global developmental delay Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Sep 01, 2014

- -

Intellectual disability Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312704; hg19: chr2-162280263;