rs727502807

Variant names:

• chr22-50219438-T-TA
• rs727502807
• NM_020461.4:c.4333_4334insT

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_020461.4(TUBGCP6):​c.4333_4334insT​(p.His1445LeufsTer24) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TUBGCP6 NM_020461.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.26
• Publications: 1 publications found

Genes affected

TUBGCP6 (HGNC:18127): (tubulin gamma complex component 6) The protein encoded by this gene is part of a large multisubunit complex required for microtubule nucleation at the centrosome. [provided by RefSeq, Jul 2008]

TUBGCP6 Gene-Disease associations (from GenCC):

• microcephaly and chorioretinopathy 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50219438-T-TA is Pathogenic according to our data. Variant chr22-50219438-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 162402.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020461.4. 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
	TUBGCP6	NM_020461.4	MANE Select	c.4333_4334insT	p.His1445LeufsTer24	frameshift	Exon 19 of 25	NP_065194.3	Q96RT7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TUBGCP6	ENST00000248846.10	TSL:1 MANE Select	c.4333_4334insT	p.His1445LeufsTer24	frameshift	Exon 19 of 25	ENSP00000248846.5	Q96RT7-1
	TUBGCP6	ENST00000425018.1	TSL:1	c.391_392insT	p.His131LeufsTer24	frameshift	Exon 4 of 10	ENSP00000405979.1	H7C2H5
	TUBGCP6	ENST00000439308.7	TSL:1	n.4392_4393insT		non_coding_transcript_exon	Exon 19 of 25	ENSP00000397387.2	E7EQL8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Microcephaly and chorioretinopathy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 18

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

Other links and lift over

dbSNP: rs727502807; hg19: chr22-50657867;