1-61725104-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032027.3(TM2D1):c.17C>T(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,613,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

TM2D1
NM_032027.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.13

Variant links:

Genes affected

TM2D1 (HGNC:24142): (TM2 domain containing 1) The protein encoded by this gene is a beta-amyloid peptide-binding protein. It contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily and known to be important in heterotrimeric G protein activation. Beta-amyloid peptide has been established to be a causative factor in neuron death and the consequent diminution of cognitive abilities observed in Alzheimer's disease. This protein may be a target of neurotoxic beta-amyloid peptide, and may mediate cellular vulnerability to beta-amyloid peptide toxicity through a G protein-regulated program of cell death. Several transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

TM2D1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08999163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM2D1	NM_032027.3 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 7	ENST00000606498.5	NP_114416.1	Q9BX74

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TM2D1	ENST00000606498.5 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 7	5	NM_032027.3	ENSP00000475700.1	Q9BX74
TM2D1	ENST00000371180.7 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 7	5		ENSP00000360222.2	J3KPA2
TM2D1	ENST00000371177.2 link	c.17C>T	p.Pro6Leu	missense_variant	Exon 1 of 5	5		ENSP00000475297.1	U3KPW4

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000106

AC:

AN:

244872

Hom.:

AF XY:

0.000112

AC XY:

AN XY:

133782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000139

AC:

203

AN:

1461222

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

726894

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000163

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000663

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 15, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.17C>T (p.P6L) alteration is located in exon 1 (coding exon 1) of the TM2D1 gene. This alteration results from a C to T substitution at nucleotide position 17, causing the proline (P) at amino acid position 6 to be replaced by a leucine (L). 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

0.096

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

T;T;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.57

.;T;T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.090

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

.;N;N;.

REVEL

Benign

0.082

Sift

Uncertain

0.0070

.;D;D;.

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

0.20

B;B;.;.

Vest4

0.15

MutPred

0.27

Loss of glycosylation at P6 (P = 0.0236);Loss of glycosylation at P6 (P = 0.0236);.;Loss of glycosylation at P6 (P = 0.0236);

MVP

0.13

MPC

0.27

ClinPred

0.11

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.053

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over