15-101651711-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 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. V52F) 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
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058091164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_078474.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM2D3	NM_078474.3	MANE Select	c.154G>A	p.Val52Ile	missense	Exon 2 of 6	NP_510883.2	Q9BRN9-1
	TM2D3	NM_001308026.2		c.154G>A	p.Val52Ile	missense	Exon 2 of 6	NP_001294955.1	H0YNS4
	TM2D3	NM_025141.4		c.91+560G>A		intron	N/A	NP_079417.2	Q9BRN9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM2D3	ENST00000333202.8	TSL:1 MANE Select	c.154G>A	p.Val52Ile	missense	Exon 2 of 6	ENSP00000330433.3	Q9BRN9-1
	TM2D3	ENST00000347970.7	TSL:1	c.91+560G>A		intron	N/A	ENSP00000327584.3	Q9BRN9-2
	TM2D3	ENST00000559107.5	TSL:3	c.154G>A	p.Val52Ile	missense	Exon 2 of 6	ENSP00000454131.1	H0YNS4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.15
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.050
Sift	Benign	0.38	T
Sift4G	Benign	0.32	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.17		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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs756600721; hg19: chr15-102191914;