15-101645162-C-T

Variant names:

• chr15-101645162-C-T
• rs775031625
• NM_078474.3:c.503G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_078474.3(TM2D3):​c.503G>A​(p.Gly168Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000111 in 1,446,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: TM2D3 NM_078474.3 missense, splice_region
• Scores: Splicing: ADA: 0.9977
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.87

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM2D3	NM_078474.3	c.503G>A	p.Gly168Asp	missense_variant, splice_region_variant	Exon 5 of 6	ENST00000333202.8	NP_510883.2
TM2D3	NM_025141.4	c.425G>A	p.Gly142Asp	missense_variant, splice_region_variant	Exon 4 of 5		NP_079417.2
TM2D3	NM_001308026.2	c.503G>A	p.Gly168Asp	missense_variant, splice_region_variant	Exon 5 of 6		NP_001294955.1
TM2D3	NM_001307960.2	c.425G>A	p.Gly142Asp	missense_variant, splice_region_variant	Exon 4 of 5		NP_001294889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM2D3	ENST00000333202.8	c.503G>A	p.Gly168Asp	missense_variant, splice_region_variant	Exon 5 of 6	1	NM_078474.3	ENSP00000330433.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000131 AC: 3 AN: 228582 Hom.: 0 AF XY: 0.0000243 AC XY: 3 AN XY: 123598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000378

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1446406 Hom.: 0 Cov.: 30 AF XY: 0.0000111 AC XY: 8 AN XY: 719278

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000479

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000996

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000390 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;T;.;T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D;D;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.96
MVP		0.13
MPC		0.46
ClinPred		0.92	D
GERP RS		6.1
Varity_R		0.85
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.010		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: rs775031625; hg19: chr15-102185365;