Genetic Variant TMTC4:p.Gly719Arg (chr13-100605122-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_032813.5(TMTC4):c.2155G>C(p.Gly719Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,610,502 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

TMTC4
NM_032813.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.56

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMTC4	NM_032813.5 link	c.2155G>C	p.Gly719Arg	missense_variant	Exon 19 of 19	ENST00000342624.10	NP_116202.2	Q5T4D3-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMTC4	ENST00000342624.10 link	c.2155G>C	p.Gly719Arg	missense_variant	Exon 19 of 19	2	NM_032813.5	ENSP00000343871.5	Q5T4D3-3
TMTC4	ENST00000376234.7 link	c.2098G>C	p.Gly700Arg	missense_variant	Exon 18 of 18	1		ENSP00000365408.3	Q5T4D3-1
TMTC4	ENST00000328767.9 link	c.1765G>C	p.Gly589Arg	missense_variant	Exon 16 of 16	2		ENSP00000365409.2	Q5T4D3-4

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000283

AC:

AN:

247038

Hom.:

AF XY:

0.0000299

AC XY:

AN XY:

133592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000387

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1458348

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

725452

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000769

Gnomad4 EAS exome

AF:

0.000456

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2155G>C (p.G719R) alteration is located in exon 19 (coding exon 18) of the TMTC4 gene. This alteration results from a G to C substitution at nucleotide position 2155, causing the glycine (G) at amino acid position 719 to be replaced by an arginine (R). 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

Uncertain

0.54

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.027

T;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.50

T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.8

M;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Uncertain

0.51

Sift

Benign

0.052

T;D;D

Sift4G

Benign

0.085

T;T;T

Polyphen

0.80

P;P;.

Vest4

0.63

MutPred

0.72

Gain of MoRF binding (P = 0.0158);.;.;

MVP

0.92

MPC

0.39

ClinPred

0.78

GERP RS

6.2

Varity_R

0.38

gMVP

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over