Genetic Variant NM_032027.3:c.442T>G (chr1-61694768-A-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_032027.3(TM2D1):c.442T>G(p.Leu148Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,592,928 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 1 hom. )

Consequence

TM2D1
NM_032027.3 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.01

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2908907).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032027.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TM2D1	NM_032027.3	MANE Select	c.442T>G	p.Leu148Val	missense splice_region	Exon 5 of 7	NP_114416.1	Q9BX74
TM2D1	NR_135160.2		n.463T>G		splice_region non_coding_transcript_exon	Exon 5 of 8
TM2D1	NR_135162.2		n.486T>G		splice_region non_coding_transcript_exon	Exon 5 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TM2D1	ENST00000606498.5	TSL:5 MANE Select	c.442T>G	p.Leu148Val	missense splice_region	Exon 5 of 7	ENSP00000475700.1	Q9BX74
TM2D1	ENST00000371180.7	TSL:5	c.442T>G	p.Leu148Val	missense splice_region	Exon 5 of 7	ENSP00000360222.2	Q9BX74
TM2D1	ENST00000964149.1		c.625T>G	p.Leu209Val	missense splice_region	Exon 6 of 8	ENSP00000634208.1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000438

AC:

AN:

228316

AF XY:

0.0000566

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000236

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000943

Gnomad OTH exome

AF:

0.000182

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1440806

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

715926

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32606

American (AMR)

AF:

0.000268

AC:

AN:

41102

Ashkenazi Jewish (ASJ)

AF:

0.0000785

AC:

AN:

25472

East Asian (EAS)

AF:

0.00

AC:

AN:

39196

South Asian (SAS)

AF:

0.0000247

AC:

AN:

80846

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52936

Middle Eastern (MID)

AF:

0.000527

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1103428

Other (OTH)

AF:

0.000118

AC:

AN:

59528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.000524

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67988

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.0000331

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.0056

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.89

PhyloP100

2.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.36

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.059

Polyphen

1.0

Vest4

0.54

MutPred

0.54

Gain of methylation at K150 (P = 0.0562)

MVP

0.43

MPC

0.62

ClinPred

0.39

GERP RS

2.1

Varity_R

0.33

gMVP

0.68

Mutation Taster

=63/37

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over