13-100606423-G-A

Position:

• chr13-100606423-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032813.5(TMTC4):​c.2069C>T​(p.Ser690Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMTC4 NM_032813.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.11

Genes affected

TMTC4 (HGNC:25904): (transmembrane O-mannosyltransferase targeting cadherins 4) This gene encodes a transmembrane protein that belongs to family of proteins containing an N-terminal transmembrane domain and a C-terminal tetratricopeptide repeat (TPR) domain. TPR domains mediate protein-protein interactions in various cellular processes, such as synaptic vesicle fusion, protein folding, and protein translocation. A pseudogene of this gene has been defined on chromosome 5. [provided by RefSeq, Apr 2017]

TMTC4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMTC4	NM_032813.5	c.2069C>T	p.Ser690Phe	missense_variant	18/19	ENST00000342624.10	NP_116202.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMTC4	ENST00000342624.10	c.2069C>T	p.Ser690Phe	missense_variant	18/19	2	NM_032813.5	ENSP00000343871.5
TMTC4	ENST00000376234.7	c.2012C>T	p.Ser671Phe	missense_variant	17/18	1		ENSP00000365408.3
TMTC4	ENST00000328767.9	c.1679C>T	p.Ser560Phe	missense_variant	15/16	2		ENSP00000365409.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 2024

The c.2069C>T (p.S690F) alteration is located in exon 18 (coding exon 17) of the TMTC4 gene. This alteration results from a C to T substitution at nucleotide position 2069, causing the serine (S) at amino acid position 690 to be replaced by a phenylalanine (F). 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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	2.0	M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;P;.
Vest4		0.81
MutPred		0.67		Loss of disorder (P = 0.0042);.;.;
MVP		0.89
MPC		0.47
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.70
gMVP		0.96

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: chr13-101258677;