rs1057517696

Variant names:

• chr12-88188870-GA-G
• rs1057517696
• NM_181783.4:c.1462delA

Variant summary

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

The NM_181783.4(TMTC3):​c.1462delA​(p.Arg488GlufsTer6) variant causes a frameshift change. 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: 32)
• Consequence: TMTC3 NM_181783.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.03
• 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: G2P, Labcorp Genetics (formerly Invitae)
• periventricular nodular heterotopia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: 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 12-88188870-GA-G is Pathogenic according to our data. Variant chr12-88188870-GA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 372273.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMTC3	NM_181783.4	c.1462delA	p.Arg488GlufsTer6	frameshift_variant	Exon 11 of 14	ENST00000266712.11	NP_861448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMTC3	ENST00000266712.11	c.1462delA	p.Arg488GlufsTer6	frameshift_variant	Exon 11 of 14	1	NM_181783.4	ENSP00000266712.6
TMTC3	ENST00000547034.5	n.*365delA		non_coding_transcript_exon_variant	Exon 12 of 12	1		ENSP00000448733.1
TMTC3	ENST00000547034.5	n.*365delA		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000448733.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lissencephaly 8 Pathogenic:1

Dec 17, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=9/191	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: rs1057517696; hg19: chr12-88582647;