Genetic Variant TM2D3:n.2001T>C (chr15-101641980-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000559891.1(TM2D3):n.2001T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 985,380 control chromosomes in the GnomAD database, including 23,416 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.17 ( 2480 hom., cov: 33)

Exomes 𝑓: 0.22 ( 20936 hom. )

Consequence

TM2D3
ENST00000559891.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.187

Publications

14 publications found

Variant links:

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]

TM2D3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TM2D3	NM_078474.3 link	c.*499T>C	3_prime_UTR_variant	Exon 6 of 6	ENST00000333202.8	NP_510883.2	Q9BRN9-1
TM2D3	NM_025141.4 link	c.*499T>C	3_prime_UTR_variant	Exon 5 of 5		NP_079417.2	Q9BRN9-2
TM2D3	NM_001308026.2 link	c.578+3107T>C	intron_variant	Intron 5 of 5		NP_001294955.1	H0YNS4B4DLL2
TM2D3	NM_001307960.2 link	c.500+3107T>C	intron_variant	Intron 4 of 4		NP_001294889.1	E7EPS7B4DLL2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM2D3	ENST00000333202.8 link	c.*499T>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_078474.3	ENSP00000330433.3		Q9BRN9-1

Frequencies

GnomAD3 genomes

AF:

0.171

AC:

26085

AN:

152160

Hom.:

2475

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.206

Gnomad AMR

AF:

0.174

Gnomad ASJ

AF:

0.138

Gnomad EAS

AF:

0.00845

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.212

Gnomad OTH

AF:

0.161

GnomAD4 exome

AF:

0.221

AC:

184371

AN:

833104

Hom.:

20936

Cov.:

AF XY:

0.221

AC XY:

85164

AN XY:

384754

show subpopulations

African (AFR)

AF:

0.133

AC:

2101

AN:

15786

American (AMR)

AF:

0.144

AC:

142

AN:

984

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

715

AN:

5152

East Asian (EAS)

AF:

0.00358

AC:

AN:

3630

South Asian (SAS)

AF:

0.138

AC:

2293

AN:

16568

European-Finnish (FIN)

AF:

0.182

AC:

AN:

280

Middle Eastern (MID)

AF:

0.152

AC:

247

AN:

1620

European-Non Finnish (NFE)

AF:

0.228

AC:

173761

AN:

761794

Other (OTH)

AF:

0.185

AC:

5048

AN:

27290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

7002

14004

21005

28007

35009

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8054

16108

24162

32216

40270

<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:

0.171

AC:

26106

AN:

152276

Hom.:

2480

Cov.:

AF XY:

0.166

AC XY:

12366

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.136

AC:

5655

AN:

41560

American (AMR)

AF:

0.173

AC:

2651

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

480

AN:

3472

East Asian (EAS)

AF:

0.00828

AC:

AN:

5196

South Asian (SAS)

AF:

0.137

AC:

660

AN:

4824

European-Finnish (FIN)

AF:

0.156

AC:

1652

AN:

10610

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.212

AC:

14391

AN:

67998

Other (OTH)

AF:

0.167

AC:

352

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1120

2241

3361

4482

5602

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.187

Hom.:

3662

Bravo

AF:

0.170

Asia WGS

AF:

0.119

AC:

413

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.1

(source)

DANN

Benign

0.75

PhyloP100

-0.19

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over