rs1553511216

chr2-161423815-G-GCGCCCGCAGT

Variant summary

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

The NM_006593.4(TBR1):c.1639_1648dup(p.Pro550ArgfsTer127) 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: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.304

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 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-161423815-G-GCGCCCGCAGT is Pathogenic according to our data. Variant chr2-161423815-G-GCGCCCGCAGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523683.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBR1	NM_006593.4	c.1639_1648dup	p.Pro550ArgfsTer127	frameshift_variant	6/6	ENST00000389554.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBR1	ENST00000389554.8	c.1639_1648dup	p.Pro550ArgfsTer127	frameshift_variant	6/6	1	NM_006593.4	P1
TBR1	ENST00000410035.1	c.778_787dup	p.Pro263ArgfsTer127	frameshift_variant	5/5	2
TBR1	ENST00000463544.1	n.7117_7126dup		non_coding_transcript_exon_variant	2/2	2
TBR1	ENST00000411412.5			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Apr 07, 2017

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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: rs1553511216; hg19: chr2-162280326;