15-101651711-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_078474.3(TM2D3):​c.154G>A​(p.Val52Ile) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V52L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

TM2D3
NM_078474.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.148
Variant links:
Genes affected
TM2D3 (HGNC:24128): (TM2 domain containing 3) The protein encoded by this gene contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily. This protein has sequence and structural similarities to the beta-amyloid binding protein (BBP), but, unlike BBP, it does not regulate a response to beta-amyloid peptide. This protein may have regulatory roles in cell death or proliferation signal cascades. Several alternatively spliced transcript variants of this gene are described but the full length nature of some variants has not been determined. Multiple polyadenylation sites have been found in this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

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=0.058091164).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TM2D3NM_078474.3 linkc.154G>A p.Val52Ile missense_variant Exon 2 of 6 ENST00000333202.8 NP_510883.2 Q9BRN9-1
TM2D3NM_001308026.2 linkc.154G>A p.Val52Ile missense_variant Exon 2 of 6 NP_001294955.1 H0YNS4B4DLL2
TM2D3NM_025141.4 linkc.91+560G>A intron_variant Intron 1 of 4 NP_079417.2 Q9BRN9-2
TM2D3NM_001307960.2 linkc.91+560G>A intron_variant Intron 1 of 4 NP_001294889.1 E7EPS7B4DLL2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TM2D3ENST00000333202.8 linkc.154G>A p.Val52Ile missense_variant Exon 2 of 6 1 NM_078474.3 ENSP00000330433.3 Q9BRN9-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
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
Jan 17, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.154G>A (p.V52I) alteration is located in exon 2 (coding exon 2) of the TM2D3 gene. This alteration results from a G to A substitution at nucleotide position 154, causing the valine (V) at amino acid position 52 to be replaced by an isoleucine (I). 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
0.083
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
14
DANN
Benign
0.95
DEOGEN2
Benign
0.013
T;T
Eigen
Benign
-0.89
Eigen_PC
Benign
-0.87
FATHMM_MKL
Benign
0.019
N
LIST_S2
Benign
0.60
T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.058
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.2
.;L
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
0.040
N;N
REVEL
Benign
0.050
Sift
Benign
0.38
T;T
Sift4G
Benign
0.32
T;T
Polyphen
0.0010
.;B
Vest4
0.12
MutPred
0.17
Loss of glycosylation at T50 (P = 0.0704);Loss of glycosylation at T50 (P = 0.0704);
MVP
0.085
MPC
0.057
ClinPred
0.029
T
GERP RS
1.6
Varity_R
0.030
gMVP
0.32

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: rs756600721; hg19: chr15-102191914; API