Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP5BS2

The NM_007180.3(TREH):c.90-9_106delTCTCTGCAGTGAGATTTACTGCCACG(p.Ser30fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,586,486 control chromosomes in the GnomAD database, including 18 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00043 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 17 hom. )

Consequence

TREH
NM_007180.3 frameshift, splice_acceptor, splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1U:1

Conservation

PhyloP100: 7.68

Publications

1 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: Likely_benign. The variant received -3 ACMG points.

PP5

Variant 11-118663422-CCGTGGCAGTAAATCTCACTGCAGAGA-C is Pathogenic according to our data. Variant chr11-118663422-CCGTGGCAGTAAATCTCACTGCAGAGA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 488190.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 66 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007180.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREH	NM_007180.3	MANE Select	c.90-9_106delTCTCTGCAGTGAGATTTACTGCCACG	p.Ser30fs	frameshift splice_acceptor splice_region intron	Exon 2 of 15	NP_009111.2
	TREH	NM_001301065.2		c.90-9_106delTCTCTGCAGTGAGATTTACTGCCACG	p.Ser30fs	frameshift splice_acceptor splice_region intron	Exon 2 of 14	NP_001287994.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TREH	ENST00000264029.9	TSL:1 MANE Select	c.90-9_106delTCTCTGCAGTGAGATTTACTGCCACG	p.Ser30fs	frameshift splice_acceptor splice_region intron	Exon 2 of 15	ENSP00000264029.5
TREH	ENST00000397925.2	TSL:1	c.90-9_106delTCTCTGCAGTGAGATTTACTGCCACG	p.Ser30fs	frameshift splice_acceptor splice_region intron	Exon 2 of 14	ENSP00000381020.2
TREH	ENST00000527558.1	TSL:4	n.153-252_153-227delTCTCTGCAGTGAGATTTACTGCCACG		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0131

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00135

AC:

278

AN:

205282

AF XY:

0.00165

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000337

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000133

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000111

Gnomad OTH exome

AF:

0.00168

GnomAD4 exome

AF:

0.000756

AC:

1085

AN:

1434262

Hom.:

AF XY:

0.00107

AC XY:

758

AN XY:

710424

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000304

AC:

AN:

32926

American (AMR)

AF:

0.0000245

AC:

AN:

40798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25538

East Asian (EAS)

AF:

0.000104

AC:

AN:

38594

South Asian (SAS)

AF:

0.0123

AC:

999

AN:

81416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51690

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00000455

AC:

AN:

1098052

Other (OTH)

AF:

0.00114

AC:

AN:

59500

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.364

Heterozygous variant carriers

117

176

234

293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000434

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41518

American (AMR)

AF:

0.000196

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0131

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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:

0.000304

Hom.:

Bravo

AF:

0.000151

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

alpha, alpha-Trehalase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.7

Mutation Taster

=134/66

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs527655595

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over