13-100612442-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032813.5(TMTC4):ā€‹c.2020A>Gā€‹(p.Met674Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,611,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00039 ( 0 hom., cov: 33)
Exomes š‘“: 0.00012 ( 0 hom. )

Consequence

TMTC4
NM_032813.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.62
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.11925718).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TMTC4NM_032813.5 linkc.2020A>G p.Met674Val missense_variant 17/19 ENST00000342624.10 NP_116202.2 Q5T4D3-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TMTC4ENST00000342624.10 linkc.2020A>G p.Met674Val missense_variant 17/192 NM_032813.5 ENSP00000343871.5 Q5T4D3-3
TMTC4ENST00000376234.7 linkc.1963A>G p.Met655Val missense_variant 16/181 ENSP00000365408.3 Q5T4D3-1
TMTC4ENST00000328767.9 linkc.1630A>G p.Met544Val missense_variant 14/162 ENSP00000365409.2 Q5T4D3-4

Frequencies

GnomAD3 genomes
AF:
0.000394
AC:
60
AN:
152204
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00135
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000141
AC:
35
AN:
247828
Hom.:
0
AF XY:
0.0000821
AC XY:
11
AN XY:
133970
show subpopulations
Gnomad AFR exome
AF:
0.000992
Gnomad AMR exome
AF:
0.0000905
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:
0.000142
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000121
AC:
177
AN:
1458750
Hom.:
0
Cov.:
32
AF XY:
0.000107
AC XY:
78
AN XY:
725652
show subpopulations
Gnomad4 AFR exome
AF:
0.000869
Gnomad4 AMR exome
AF:
0.0000453
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000126
Gnomad4 OTH exome
AF:
0.0000829
GnomAD4 genome
AF:
0.000394
AC:
60
AN:
152322
Hom.:
0
Cov.:
33
AF XY:
0.000228
AC XY:
17
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.00135
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00139
Hom.:
0
Bravo
AF:
0.000419
ESP6500AA
AF:
0.00136
AC:
6
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000206
AC:
25

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 12, 2022The c.2020A>G (p.M674V) alteration is located in exon 17 (coding exon 16) of the TMTC4 gene. This alteration results from a A to G substitution at nucleotide position 2020, causing the methionine (M) at amino acid position 674 to be replaced by a valine (V). 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
Benign
0.24
BayesDel_addAF
Benign
-0.072
T
BayesDel_noAF
Uncertain
0.070
CADD
Benign
21
DANN
Benign
0.93
DEOGEN2
Benign
0.019
T;.;.
Eigen
Benign
-0.039
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.12
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L;.;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.3
N;N;N
REVEL
Benign
0.25
Sift
Benign
0.43
T;T;T
Sift4G
Benign
0.50
T;T;T
Polyphen
0.075
B;B;.
Vest4
0.82
MVP
0.50
MPC
0.10
ClinPred
0.043
T
GERP RS
5.7
Varity_R
0.31
gMVP
0.79

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.

Other links and lift over

dbSNP: rs144940475; hg19: chr13-101264696; COSMIC: COSV60892625; API