rs1553511175

Variant names:

• chr2-161423547-ACG-CA
• rs1553511175
• NM_006593.4:c.1369_1371delACGinsCA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006593.4(TBR1):​c.1369_1371delACGinsCA​(p.Thr457GlnfsTer30) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T457R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TBR1 NM_006593.4 frameshift, missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.32
• 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
• intellectual developmental disorder with autism and speech delay

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• occipital pachygyria and polymicrogyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000224076 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-161423547-ACG-CA is Pathogenic according to our data. Variant chr2-161423547-ACG-CA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 523682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBR1	NM_006593.4	MANE Select	c.1369_1371delACGinsCA	p.Thr457GlnfsTer30	frameshift missense	Exon 6 of 6	NP_006584.1	Q16650-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBR1	ENST00000389554.8	TSL:1 MANE Select	c.1369_1371delACGinsCA	p.Thr457GlnfsTer30	frameshift missense	Exon 6 of 6	ENSP00000374205.3	Q16650-1
	TBR1	ENST00000410035.1	TSL:2	c.508_510delACGinsCA	p.Thr170GlnfsTer30	frameshift missense	Exon 5 of 5	ENSP00000387023.1	Q16650-2
	TBR1	ENST00000411412.5	TSL:5	c.514-45_514-43delACGinsCA		intron	N/A	ENSP00000393934.1	H7C0B1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Autistic behavior;C2237142:Moderate global developmental delay (1)
1	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3

Splicing

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

Other links and lift over

dbSNP: rs1553511175; hg19: chr2-162280058;