12-88153423-C-T

Variant names:

• chr12-88153423-C-T
• NM_181783.4:c.322C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181783.4(TMTC3):​c.322C>T​(p.Leu108Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L108L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMTC3 NM_181783.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.83
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3691756).

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.322C>T	p.Leu108Phe	missense	Exon 3 of 14	NP_861448.2	Q6ZXV5-2
	TMTC3	NM_001366574.1		c.142C>T	p.Leu48Phe	missense	Exon 3 of 14	NP_001353503.1
	TMTC3	NM_001366580.1		c.55C>T	p.Leu19Phe	missense	Exon 2 of 13	NP_001353509.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMTC3	ENST00000266712.11	TSL:1 MANE Select	c.322C>T	p.Leu108Phe	missense	Exon 3 of 14	ENSP00000266712.6	Q6ZXV5-2
	TMTC3	ENST00000547034.5	TSL:1	n.322C>T		non_coding_transcript_exon	Exon 3 of 12	ENSP00000448733.1	F8VRY4
	TMTC3	ENST00000869786.1		c.322C>T	p.Leu108Phe	missense	Exon 3 of 14	ENSP00000539845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.065	T
MutationAssessor	Benign	0.93	L
PhyloP100		5.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.43
Sift	Benign	0.57	T
Sift4G	Benign	0.68	T
Polyphen		0.068	B
Vest4		0.71
MutPred		0.48		Gain of catalytic residue at F107 (P = 0.0089)
MVP		0.85
MPC		0.42
ClinPred		0.70	D
GERP RS		5.9
gMVP		0.54
Mutation Taster		=50/50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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

hg19: chr12-88547200;