dbSNP rs34978247: TREH:p.Lys140Arg (chr11-118662885-T-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_007180.3(TREH):c.419A>G(p.Lys140Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00563 in 1,584,382 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K140Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0036 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 24 hom. )

Consequence

TREH
NM_007180.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.44

Publications

8 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007879496).

BP6

Variant 11-118662885-T-C is Benign according to our data. Variant chr11-118662885-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 377170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 550 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREH	NM_007180.3 link	c.419A>G	p.Lys140Arg	missense_variant	Exon 4 of 15	ENST00000264029.9	NP_009111.2	O43280-1
TREH	NM_001301065.2 link	c.419A>G	p.Lys140Arg	missense_variant	Exon 4 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.419A>G	p.Lys140Arg	missense_variant	Exon 4 of 15	1	NM_007180.3	ENSP00000264029.5		O43280-1

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

552

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00607

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00349

AC:

708

AN:

202860

AF XY:

0.00344

show subpopulations

Gnomad AFR exome

AF:

0.00103

Gnomad AMR exome

AF:

0.00238

Gnomad ASJ exome

AF:

0.00681

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00142

Gnomad NFE exome

AF:

0.00574

Gnomad OTH exome

AF:

0.00436

GnomAD4 exome

AF:

0.00584

AC:

8370

AN:

1432030

Hom.:

Cov.:

AF XY:

0.00561

AC XY:

3979

AN XY:

709552

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

32828

American (AMR)

AF:

0.00263

AC:

104

AN:

39614

Ashkenazi Jewish (ASJ)

AF:

0.00679

AC:

173

AN:

25492

East Asian (EAS)

AF:

0.00

AC:

AN:

38178

South Asian (SAS)

AF:

0.000280

AC:

AN:

82268

European-Finnish (FIN)

AF:

0.00143

AC:

AN:

51648

Middle Eastern (MID)

AF:

0.00349

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00698

AC:

7662

AN:

1096944

Other (OTH)

AF:

0.00462

AC:

274

AN:

59324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

434

868

1301

1735

2169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.00361

AC:

550

AN:

152352

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

234

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

41596

American (AMR)

AF:

0.00209

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00188

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00607

AC:

413

AN:

68032

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00529

Hom.:

Bravo

AF:

0.00380

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000753

AC:

ESP6500EA

AF:

0.00577

AC:

ExAC

AF:

0.00280

AC:

337

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 17, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0079

T;T

MetaSVM

Benign

-0.99

PhyloP100

2.4

PrimateAI

Benign

0.37

PROVEAN

Benign

1.6

N;N

REVEL

Benign

0.031

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0040

B;.

Vest4

0.17

MVP

0.030

MPC

0.029

ClinPred

0.0061

GERP RS

2.4

Varity_R

0.063

gMVP

0.38

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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