19-54165526-C-T
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_144686.4(TMC4):c.838G>A(p.Glu280Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,611,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
TMC4
NM_144686.4 missense
NM_144686.4 missense
Scores
1
13
Clinical Significance
Conservation
PhyloP100: 4.67
Genes affected
TMC4 (HGNC:22998): (transmembrane channel like 4) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.038234353).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMC4 | NM_144686.4 | c.838G>A | p.Glu280Lys | missense_variant | 6/15 | ENST00000619895.5 | |
TMC4 | NM_001145303.3 | c.856G>A | p.Glu286Lys | missense_variant | 6/15 | ||
TMC4 | XM_011526486.3 | c.816-2367G>A | intron_variant | ||||
TMC4 | XR_935741.3 | n.899G>A | non_coding_transcript_exon_variant | 6/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMC4 | ENST00000619895.5 | c.838G>A | p.Glu280Lys | missense_variant | 6/15 | 1 | NM_144686.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000689 AC: 17AN: 246640Hom.: 0 AF XY: 0.0000671 AC XY: 9AN XY: 134064
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GnomAD4 exome AF: 0.0000356 AC: 52AN: 1459174Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26AN XY: 725554
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152230Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74374
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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 | Jul 11, 2023 | The c.856G>A (p.E286K) alteration is located in exon 6 (coding exon 6) of the TMC4 gene. This alteration results from a G to A substitution at nucleotide position 856, causing the glutamic acid (E) at amino acid position 286 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
N;N
PrimateAI
Benign
T
Sift4G
Benign
T;T
Vest4
MutPred
0.36
.;Gain of ubiquitination at E286 (P = 0.0162);
MVP
ClinPred
T
GERP RS
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