12-88148344-C-T

Variant names:

• chr12-88148344-C-T
• rs1565941864
• NM_181783.4:c.29C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181783.4(TMTC3):​c.29C>T​(p.Thr10Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TMTC3 NM_181783.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094840676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMTC3	NM_181783.4	c.29C>T	p.Thr10Ile	missense_variant	Exon 2 of 14	ENST00000266712.11	NP_861448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMTC3	ENST00000266712.11	c.29C>T	p.Thr10Ile	missense_variant	Exon 2 of 14	1	NM_181783.4	ENSP00000266712.6
TMTC3	ENST00000547034.5	n.29C>T		non_coding_transcript_exon_variant	Exon 2 of 12	1		ENSP00000448733.1
TMTC3	ENST00000549011.5	c.29C>T	p.Thr10Ile	missense_variant	Exon 2 of 4	4		ENSP00000447640.1
TMTC3	ENST00000551088.1	c.29C>T	p.Thr10Ile	missense_variant	Exon 2 of 5	3		ENSP00000448566.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250658 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460626 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726608

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.29C>T (p.T10I) alteration is located in exon 2 (coding exon 1) of the TMTC3 gene. This alteration results from a C to T substitution at nucleotide position 29, causing the threonine (T) at amino acid position 10 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0069	T;.;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.095	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	.;N;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.32	N;N;N
REVEL	Benign	0.068
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.0040	.;B;.
Vest4		0.17
MutPred		0.38		Gain of catalytic residue at V15 (P = 0);Gain of catalytic residue at V15 (P = 0);Gain of catalytic residue at V15 (P = 0);
MVP		0.51
MPC		0.34
ClinPred		0.069	T
GERP RS		3.4
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1565941864; hg19: chr12-88542121;