rs483352922

Variant names:

• chr6-13307726-TA-T
• rs483352922
• NM_016495.6:c.538delT

Variant summary

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

The NM_016495.6(TBC1D7):​c.538delT​(p.Tyr180ThrfsTer2) 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: 33)
• Consequence: TBC1D7 NM_016495.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.75
• Publications: 3 publications found

Genes affected

TBC1D7 (HGNC:21066): (TBC1 domain family member 7) This gene encodes a member of the TBC-domain containing protein family. The encoded protein functions as a subunit of the tuberous sclerosis TSC1-TSC2 complex which plays a role in the regulation of cellular growth and differentiation. Mutations in this gene have been associated with autosomal recessive megalencephaly. Alternative splicing results in multiple transcript variants. Naturally occurring readthrough transcription occurs between this locus and downstream LOC100130357. [provided by RefSeq, Jan 2016]

TBC1D7 Gene-Disease associations (from GenCC):

• macrocephaly/megalencephaly syndrome, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

TBC1D7-LOC100130357 (HGNC:):

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 6-13307726-TA-T is Pathogenic according to our data. Variant chr6-13307726-TA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 89031.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016495.6. 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
	TBC1D7	NM_016495.6	MANE Select	c.538delT	p.Tyr180ThrfsTer2	frameshift	Exon 6 of 8	NP_057579.1	Q9P0N9-1
	TBC1D7	NM_001143964.4		c.538delT	p.Tyr180ThrfsTer2	frameshift	Exon 6 of 8	NP_001137436.1	Q9P0N9-1
	TBC1D7	NM_001143965.4		c.538delT	p.Tyr180ThrfsTer2	frameshift	Exon 6 of 8	NP_001137437.1	Q9P0N9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D7	ENST00000379300.8	TSL:1 MANE Select	c.538delT	p.Tyr180ThrfsTer2	frameshift	Exon 6 of 8	ENSP00000368602.3	Q9P0N9-1
	TBC1D7	ENST00000356436.8	TSL:1	c.538delT	p.Tyr180ThrfsTer2	frameshift	Exon 6 of 8	ENSP00000348813.4	Q9P0N9-1
	TBC1D7	ENST00000379307.6	TSL:1	c.457delT	p.Tyr153ThrfsTer2	frameshift	Exon 5 of 7	ENSP00000368609.2	Q9P0N9-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Macrocephaly/megalencephaly syndrome, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs483352922; hg19: chr6-13307958;