dbSNP rs2276065: TREH:p.Thr389Ala (chr11-118659902-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_007180.3(TREH):c.1165A>G(p.Thr389Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 1,551,634 control chromosomes in the GnomAD database, including 42,148 homozygotes. 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 Benign (no stars).

Frequency

Genomes: 𝑓 0.20 ( 3328 hom., cov: 32)

Exomes 𝑓: 0.23 ( 38820 hom. )

Consequence

TREH
NM_007180.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.897

Publications

37 publications found

Variant links:

Genes affected

TREH (HGNC:12266): (trehalase) This gene encodes an enzyme that hydrolyses trehalose, a disaccharide formed from two glucose molecules found mainly in fungi, plants, and insects. A partial duplication of this gene is located adjacent to this locus on chromosome 11. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

TREH Gene-Disease associations (from GenCC):

diarrhea-vomiting due to trehalase deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TREH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010524929).

BP6

Variant 11-118659902-T-C is Benign according to our data. Variant chr11-118659902-T-C is described in ClinVar as Benign. ClinVar VariationId is 3060563.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREH	NM_007180.3 link	c.1165A>G	p.Thr389Ala	missense_variant	Exon 11 of 15	ENST00000264029.9	NP_009111.2	O43280-1
TREH	NM_001301065.2 link	c.1072A>G	p.Thr358Ala	missense_variant	Exon 10 of 14		NP_001287994.1	O43280-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREH	ENST00000264029.9 link	c.1165A>G	p.Thr389Ala	missense_variant	Exon 11 of 15	1	NM_007180.3	ENSP00000264029.5		O43280-1

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30699

AN:

152062

Hom.:

3326

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.174

Gnomad AMR

AF:

0.238

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.243

Gnomad SAS

AF:

0.357

Gnomad FIN

AF:

0.219

Gnomad MID

AF:

0.220

Gnomad NFE

AF:

0.233

Gnomad OTH

AF:

0.195

GnomAD2 exomes

AF:

0.235

AC:

36939

AN:

157018

AF XY:

0.245

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.209

Gnomad ASJ exome

AF:

0.202

Gnomad EAS exome

AF:

0.251

Gnomad FIN exome

AF:

0.223

Gnomad NFE exome

AF:

0.229

Gnomad OTH exome

AF:

0.228

GnomAD4 exome

AF:

0.232

AC:

324371

AN:

1399454

Hom.:

38820

Cov.:

AF XY:

0.236

AC XY:

162566

AN XY:

690246

show subpopulations

African (AFR)

AF:

0.104

AC:

3281

AN:

31602

American (AMR)

AF:

0.211

AC:

7545

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

5117

AN:

25182

East Asian (EAS)

AF:

0.220

AC:

7852

AN:

35738

South Asian (SAS)

AF:

0.338

AC:

26782

AN:

79240

European-Finnish (FIN)

AF:

0.225

AC:

11080

AN:

49288

Middle Eastern (MID)

AF:

0.219

AC:

1250

AN:

5698

European-Non Finnish (NFE)

AF:

0.230

AC:

247985

AN:

1078992

Other (OTH)

AF:

0.232

AC:

13479

AN:

58010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

16207

32413

48620

64826

81033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8648

17296

25944

34592

43240

<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:

0.202

AC:

30709

AN:

152180

Hom.:

3328

Cov.:

AF XY:

0.205

AC XY:

15268

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.111

AC:

4627

AN:

41528

American (AMR)

AF:

0.238

AC:

3632

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

701

AN:

3472

East Asian (EAS)

AF:

0.243

AC:

1255

AN:

5160

South Asian (SAS)

AF:

0.358

AC:

1728

AN:

4824

European-Finnish (FIN)

AF:

0.219

AC:

2320

AN:

10604

Middle Eastern (MID)

AF:

0.219

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.233

AC:

15806

AN:

67980

Other (OTH)

AF:

0.197

AC:

417

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1286

2571

3857

5142

6428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

340

680

1020

1360

1700

<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:

0.199

Hom.:

2126

Bravo

AF:

0.193

TwinsUK

AF:

0.217

AC:

806

ALSPAC

AF:

0.221

AC:

850

ESP6500AA

AF:

0.103

AC:

379

ESP6500EA

AF:

0.193

AC:

1504

ExAC

AF:

0.145

AC:

9461

Asia WGS

AF:

0.269

AC:

935

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TREH-related disorder

Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.36

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.030

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.00039

LIST_S2

Benign

0.087

T;T

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-1.0

PhyloP100

0.90

PrimateAI

Benign

0.35

PROVEAN

Benign

1.5

N;N

REVEL

Benign

0.098

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.0020

MPC

0.030

ClinPred

0.0019

GERP RS

3.8

Varity_R

0.047

gMVP

0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over