12-29604202-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP3BP4_Moderate
The NM_001193451.2(TMTC1):c.1226C>T(p.Ala409Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,613,656 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 1 hom. )
Consequence
TMTC1
NM_001193451.2 missense
NM_001193451.2 missense
Scores
10
4
3
Clinical Significance
Conservation
PhyloP100: 9.18
Genes affected
TMTC1 (HGNC:24099): (transmembrane O-mannosyltransferase targeting cadherins 1) Enables mannosyltransferase activity. Involved in protein O-linked mannosylation. Predicted to be located in endoplasmic reticulum. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.16498294).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMTC1 | NM_001193451.2 | c.1226C>T | p.Ala409Val | missense_variant | 7/18 | ENST00000539277.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMTC1 | ENST00000539277.6 | c.1226C>T | p.Ala409Val | missense_variant | 7/18 | 1 | NM_001193451.2 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152100Hom.: 0 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.000247 AC: 62AN: 251140Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135728
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GnomAD4 exome AF: 0.000166 AC: 242AN: 1461556Hom.: 1 Cov.: 31 AF XY: 0.000180 AC XY: 131AN XY: 727082
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GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74286
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ExAC
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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 submitter | clinical testing | Ambry Genetics | Apr 25, 2022 | The c.1226C>T (p.A409V) alteration is located in exon 7 (coding exon 7) of the TMTC1 gene. This alteration results from a C to T substitution at nucleotide position 1226, causing the alanine (A) at amino acid position 409 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
1.0, 1.0
.;D;.;D;.
Vest4
MVP
MPC
0.73
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at