rs1057519417

Variant names:

• chr12-88194862-C-CTT
• rs1057519417
• NM_181783.4:c.1959_1960insTT

Variant summary

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

The NM_181783.4(TMTC3):​c.1959_1960insTT​(p.Arg654LeufsTer6) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMTC3 NM_181783.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.212
• Publications: 1 publications found

Genes affected

TMTC3 (HGNC:26899): (transmembrane O-mannosyltransferase targeting cadherins 3) This gene encodes a protein that belongs to the transmembrane and tetratricopeptide repeat-containing protein family. [provided by RefSeq, May 2010]

TMTC3 Gene-Disease associations (from GenCC):

• lissencephaly 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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. Fraction of 0.286 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-88194862-C-CTT is Pathogenic according to our data. Variant chr12-88194862-C-CTT is described in ClinVar as Pathogenic. ClinVar VariationId is 372275.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181783.4. 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
	TMTC3	NM_181783.4	MANE Select	c.1959_1960insTT	p.Arg654LeufsTer6	frameshift	Exon 14 of 14	NP_861448.2	Q6ZXV5-2
	TMTC3	NM_001366574.1		c.1779_1780insTT	p.Arg594LeufsTer6	frameshift	Exon 14 of 14	NP_001353503.1
	TMTC3	NM_001366579.1		c.1740_1741insTT	p.Arg581LeufsTer6	frameshift	Exon 13 of 13	NP_001353508.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC3	ENST00000266712.11	TSL:1 MANE Select	c.1959_1960insTT	p.Arg654LeufsTer6	frameshift	Exon 14 of 14	ENSP00000266712.6	Q6ZXV5-2
	TMTC3	ENST00000869786.1		c.1959_1960insTT	p.Arg654LeufsTer6	frameshift	Exon 14 of 14	ENSP00000539845.1
	TMTC3	ENST00000920416.1		c.1959_1960insTT	p.Arg654LeufsTer6	frameshift	Exon 15 of 15	ENSP00000590475.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Lissencephaly 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057519417; hg19: chr12-88588639;