rs1553511224

Variant names:

• chr2-161423825-T-TC
• rs1553511224
• NM_006593.4:c.1652dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006593.4(TBR1):​c.1652dupC​(p.Gln552AlafsTer122) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000151 in 1,323,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TBR1 NM_006593.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.16
• Publications: 0 publications found

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]

TBR1 Gene-Disease associations (from GenCC):

• autism

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• occipital pachygyria and polymicrogyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000224076 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-161423825-T-TC is Pathogenic according to our data. Variant chr2-161423825-T-TC is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 523684.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006593.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBR1	NM_006593.4	MANE Select	c.1652dupC	p.Gln552AlafsTer122	frameshift	Exon 6 of 6	NP_006584.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBR1	ENST00000389554.8	TSL:1 MANE Select	c.1652dupC	p.Gln552AlafsTer122	frameshift	Exon 6 of 6	ENSP00000374205.3
	TBR1	ENST00000410035.1	TSL:2	c.791dupC	p.Gln265AlafsTer122	frameshift	Exon 5 of 5	ENSP00000387023.1
	TBR1	ENST00000463544.1	TSL:2	n.7130dupC		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1323612 Hom.: 0 Cov.: 38 AF XY: 0.00000153 AC XY: 1 AN XY: 651534

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26706

American (AMR) AF: 0.00 AC: 0 AN: 28330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23004

East Asian (EAS) AF: 0.00 AC: 0 AN: 29378

South Asian (SAS) AF: 0.00 AC: 0 AN: 72212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3914

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1049536

Other (OTH) AF: 0.00 AC: 0 AN: 54940

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

EEG abnormality;C0424503:Abnormal facial shape;C0431380:Cortical dysplasia;C0575081:Gait disturbance;C1837397:Severe global developmental delay;C1854882:Absent speech;C1858120:Generalized hypotonia;C4022524:Hypoplastic anterior commissure;C4476822:Hypoplastic hippocampus;C5826341:Inflexible adherence to routines Pathogenic:1

Dec 01, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Severe global developmental delay Pathogenic:1

Mar 16, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.2

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: rs1553511224; hg19: chr2-162280336;