rs976377433

Variant names:

• chr15-101642558-A-C
• rs976377433
• NM_078474.3:c.665T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-101642558-A-C
• chr15-101642558-A-G

Variant summary

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

The NM_078474.3(TM2D3):​c.665T>G​(p.Leu222Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TM2D3 NM_078474.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.08

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, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM2D3	NM_078474.3	c.665T>G	p.Leu222Arg	missense_variant	Exon 6 of 6	ENST00000333202.8	NP_510883.2
TM2D3	NM_025141.4	c.587T>G	p.Leu196Arg	missense_variant	Exon 5 of 5		NP_079417.2
TM2D3	NM_001308026.2	c.578+2529T>G		intron_variant	Intron 5 of 5		NP_001294955.1
TM2D3	NM_001307960.2	c.500+2529T>G		intron_variant	Intron 4 of 4		NP_001294889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM2D3	ENST00000333202.8	c.665T>G	p.Leu222Arg	missense_variant	Exon 6 of 6	1	NM_078474.3	ENSP00000330433.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460906 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726726

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.0	.;H;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.83		.;Gain of methylation at L222 (P = 0.01);.;
MVP		0.24
MPC		0.49
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.98

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: rs976377433; hg19: chr15-102182761;