NM_078474.3:c.503G>A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

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. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• 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: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 6.87
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 15-101645162-C-T is Pathogenic according to our data. Variant chr15-101645162-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3370440.Status of the report is no_assertion_criteria_provided, 0 stars.

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.503G>A	p.Gly168Asp	missense splice_region	Exon 5 of 6	NP_510883.2	Q9BRN9-1
	TM2D3	NM_025141.4		c.425G>A	p.Gly142Asp	missense splice_region	Exon 4 of 5	NP_079417.2	Q9BRN9-2
	TM2D3	NM_001308026.2		c.503G>A	p.Gly168Asp	missense splice_region	Exon 5 of 6	NP_001294955.1	H0YNS4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM2D3	ENST00000333202.8	TSL:1 MANE Select	c.503G>A	p.Gly168Asp	missense splice_region	Exon 5 of 6	ENSP00000330433.3	Q9BRN9-1
	TM2D3	ENST00000347970.7	TSL:1	c.425G>A	p.Gly142Asp	missense splice_region	Exon 4 of 5	ENSP00000327584.3	Q9BRN9-2
	TM2D3	ENST00000559891.1	TSL:1	n.1261G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000131 AC: 3 AN: 228582 AF XY: 0.0000243

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32474

American (AMR) AF: 0.0000236 AC: 1 AN: 42312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25802

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.0000479 AC: 4 AN: 83454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000996 AC: 11 AN: 1104476

Other (OTH) AF: 0.00 AC: 0 AN: 59760

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000390 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	NEUROCARDIORENAL MALFORMATION SYNDROME (1)
1	-	-	TM2D3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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
Mutation Taster		=27/73	disease causing

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

Other links and lift over

dbSNP: rs775031625; hg19: chr15-102185365;