dbSNP rs1232427248: TM2D1:p.Thr74Ser (chr1-61723731-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032027.3(TM2D1):c.220A>T(p.Thr74Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000071 in 1,407,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T74A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TM2D1
NM_032027.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.77

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3120771).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM2D1	NM_032027.3 link	c.220A>T	p.Thr74Ser	missense_variant	Exon 2 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.220A>T	p.Thr74Ser	missense_variant	Exon 2 of 7	5	NM_032027.3	ENSP00000475700.1	Q9BX74
TM2D1	ENST00000371180.7 link	c.220A>T	p.Thr74Ser	missense_variant	Exon 2 of 7	5		ENSP00000360222.2	J3KPA2
TM2D1	ENST00000371177.2 link	c.220A>T	p.Thr74Ser	missense_variant	Exon 2 of 5	5		ENSP00000475297.1	U3KPW4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1407584

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

696908

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:

9.27e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

0.0098

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.023

T;T;.;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.70

.;T;T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;.;.

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.8

.;N;N;.

REVEL

Benign

0.073

Sift

Benign

0.32

.;T;T;.

Sift4G

Benign

0.32

T;T;T;T

Polyphen

0.69

P;P;.;.

Vest4

0.52

MutPred

0.24

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);

MVP

0.45

MPC

0.26

ClinPred

0.66

GERP RS

5.4

Varity_R

0.14

gMVP

0.42

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over