rs1553511224

Positions:

• chr2-161423825-T-TC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000389554.8(TBR1):​c.1652dup​(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 ENST00000389554.8 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.16

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 Likely_pathogenic. Variant got 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 5 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 id is 523684.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBR1	NM_006593.4	c.1652dup	p.Gln552AlafsTer122	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.1652dup	p.Gln552AlafsTer122	frameshift_variant	6/6	1	NM_006593.4	ENSP00000374205	P1
TBR1	ENST00000410035.1	c.791dup	p.Gln265AlafsTer122	frameshift_variant	5/5	2		ENSP00000387023
TBR1	ENST00000463544.1	n.7130dup		non_coding_transcript_exon_variant	2/2	2
TBR1	ENST00000411412.5			downstream_gene_variant		5		ENSP00000393934

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000191

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Severe 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

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Dec 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

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: rs1553511224; hg19: chr2-162280336;