15-81332623-C-A

Variant summary

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

The NM_001080532.3(TMC3):​c.3099G>T​(p.Arg1033Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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

TMC3
NM_001080532.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24
Variant links:
Genes affected
TMC3 (HGNC:22995): (transmembrane channel like 3) Predicted to enable mechanosensitive ion channel activity. Predicted to be involved in ion transmembrane transport. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]
TMC3-AS1 (HGNC:51424): (TMC3 antisense RNA 1)

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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=0.07368627).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMC3NM_001080532.3 linkc.3099G>T p.Arg1033Ser missense_variant Exon 22 of 22 ENST00000359440.6 NP_001074001.1 Q7Z5M5-1
TMC3-AS1NR_120365.1 linkn.426+82C>A intron_variant Intron 2 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMC3ENST00000359440.6 linkc.3099G>T p.Arg1033Ser missense_variant Exon 22 of 22 1 NM_001080532.3 ENSP00000352413.5 Q7Z5M5-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
82
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 05, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3099G>T (p.R1033S) alteration is located in exon 22 (coding exon 22) of the TMC3 gene. This alteration results from a G to T substitution at nucleotide position 3099, causing the arginine (R) at amino acid position 1033 to be replaced by a serine (S). 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
0.12
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
16
DANN
Benign
0.95
DEOGEN2
Benign
0.0085
.;T
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.028
D
MetaRNN
Benign
0.074
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.2
.;L
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.45
N;N
REVEL
Benign
0.049
Sift
Uncertain
0.0060
D;D
Sift4G
Uncertain
0.0080
D;D
Polyphen
0.049
.;B
Vest4
0.092
MutPred
0.19
.;Gain of phosphorylation at R1033 (P = 0.0092);
MVP
0.088
MPC
0.18
ClinPred
0.40
T
GERP RS
3.0
Varity_R
0.14
gMVP
0.12

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: chr15-81624964; API