chr12-88153417-A-G

Position:

• chr12-88153417-A-G

Variant summary

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

The NM_181783.4(TMTC3):​c.316A>G​(p.Ile106Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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: 0.0000027 (0 hom.)
• Consequence: TMTC3 NM_181783.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.956

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=0.16323781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMTC3	NM_181783.4	c.316A>G	p.Ile106Val	missense_variant	3/14	ENST00000266712.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMTC3	ENST00000266712.11	c.316A>G	p.Ile106Val	missense_variant	3/14	1	NM_181783.4	P1
TMTC3	ENST00000547034.5	c.316A>G	p.Ile106Val	missense_variant, NMD_transcript_variant	3/12	1
TMTC3	ENST00000549011.5	c.316A>G	p.Ile106Val	missense_variant	3/4	4
TMTC3	ENST00000551088.1	c.190-871A>G		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461356 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726998

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with TMTC3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 106 of the TMTC3 protein (p.Ile106Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.050	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.48	.;N
MutationTaster	Benign	0.56	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.85	N;N
REVEL	Benign	0.24
Sift	Benign	0.11	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0	.;B
Vest4		0.14
MutPred		0.53		Gain of catalytic residue at A101 (P = 0.0025);Gain of catalytic residue at A101 (P = 0.0025);
MVP		0.60
MPC		0.27
ClinPred		0.23	T
GERP RS		0.31
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-88547194;