rs869312704

Variant names:

• chr2-161423752-CGCTGCAG-C
• rs869312704
• NM_006593.4:c.1588_1594delGGCTGCA

Your query was ambiguous. Multiple possible variants found:

• chr2-161423752-CGCTGCAG-C
• chr2-161423752-CGCTGCAG-CGCTGCAGGCTGCAG

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_006593.4(TBR1):​c.1588_1594delGGCTGCA​(p.Gly530LeufsTer190) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,353,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in Lovd as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: TBR1 NM_006593.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.52

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]

ENSG00000224076 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 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 6 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-161423752-CGCTGCAG-C is Pathogenic according to our data. Variant chr2-161423752-CGCTGCAG-C is described in Lovd as [Likely_pathogenic]. Variant chr2-161423752-CGCTGCAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBR1	NM_006593.4	c.1588_1594delGGCTGCA	p.Gly530LeufsTer190	frameshift_variant	Exon 6 of 6	ENST00000389554.8	NP_006584.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBR1	ENST00000389554.8	c.1588_1594delGGCTGCA	p.Gly530LeufsTer190	frameshift_variant	Exon 6 of 6	1	NM_006593.4	ENSP00000374205.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000148 AC: 2 AN: 1353084 Hom.: 0 AF XY: 0.00000300 AC XY: 2 AN XY: 667272

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 27892

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 33350

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 23974

Gnomad4 EAS exome AF: 0.0000309 AC: 1 AN: 32362

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 75612

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 33532

Gnomad4 NFE exome AF: 9.38e-7 AC: 1 AN: 1065962

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 56324

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

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;