Genetic Variant NM_032027.3:c.146A>G (chr1-61724975-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_032027.3(TM2D1):c.146A>G(p.Glu49Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TM2D1
NM_032027.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.63

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:

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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=0.25811073).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM2D1	NM_032027.3 link	c.146A>G	p.Glu49Gly	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.146A>G	p.Glu49Gly	missense_variant	Exon 1 of 7	5	NM_032027.3	ENSP00000475700.1	Q9BX74
TM2D1	ENST00000371180.7 link	c.146A>G	p.Glu49Gly	missense_variant	Exon 1 of 7	5		ENSP00000360222.2	J3KPA2
TM2D1	ENST00000371177.2 link	c.146A>G	p.Glu49Gly	missense_variant	Exon 1 of 5	5		ENSP00000475297.1	U3KPW4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000817

AC:

AN:

244920

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133106

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451016

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719446

show subpopulations

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:

9.06e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.146A>G (p.E49G) alteration is located in exon 1 (coding exon 1) of the TM2D1 gene. This alteration results from a A to G substitution at nucleotide position 146, causing the glutamic acid (E) at amino acid position 49 to be replaced by a glycine (G). 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

0.12

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.028

T;T;.;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.20

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.69

.;T;T;T

M_CAP

Benign

0.0065

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

L;L;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.0

.;N;N;.

REVEL

Benign

0.13

Sift

Benign

0.23

.;T;D;.

Sift4G

Benign

0.30

T;T;T;T

Polyphen

0.68

P;P;.;.

Vest4

0.46

MVP

0.34

MPC

0.60

ClinPred

0.96

GERP RS

4.6

Varity_R

0.20

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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