15-101651711-C-T

Variant names:

• chr15-101651711-C-T
• rs756600721
• NM_078474.3:c.154G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.148

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]

ACMG classification

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
TM2D3	NM_078474.3	c.154G>A	p.Val52Ile	missense_variant	Exon 2 of 6	ENST00000333202.8	NP_510883.2
TM2D3	NM_001308026.2	c.154G>A	p.Val52Ile	missense_variant	Exon 2 of 6		NP_001294955.1
TM2D3	NM_025141.4	c.91+560G>A		intron_variant	Intron 1 of 4		NP_079417.2
TM2D3	NM_001307960.2	c.91+560G>A		intron_variant	Intron 1 of 4		NP_001294889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM2D3	ENST00000333202.8	c.154G>A	p.Val52Ile	missense_variant	Exon 2 of 6	1	NM_078474.3	ENSP00000330433.3

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

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

Other links and lift over

dbSNP: rs756600721; hg19: chr15-102191914;