11-118658925-T-A

Variant names:

• chr11-118658925-T-A
• rs201467126
• NM_007180.3:c.1525A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_007180.3(TREH):​c.1525A>T​(p.Lys509*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,800 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: TREH NM_007180.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREH	NM_007180.3	c.1525A>T	p.Lys509*	stop_gained	Exon 13 of 15	ENST00000264029.9	NP_009111.2
TREH	NM_001301065.2	c.1432A>T	p.Lys478*	stop_gained	Exon 12 of 14		NP_001287994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREH	ENST00000264029.9	c.1525A>T	p.Lys509*	stop_gained	Exon 13 of 15	1	NM_007180.3	ENSP00000264029.5
TREH	ENST00000397925.2	c.1432A>T	p.Lys478*	stop_gained	Exon 12 of 14	1		ENSP00000381020.2
TREH	ENST00000613915.4	n.*1302A>T		non_coding_transcript_exon_variant	Exon 11 of 13	2		ENSP00000477923.1
TREH	ENST00000613915.4	n.*1302A>T		3_prime_UTR_variant	Exon 11 of 13	2		ENSP00000477923.1

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000449 AC: 112 AN: 249248 AF XY: 0.000458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000947

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.00125 AC: 1826 AN: 1461638 Hom.: 3 Cov.: 34 AF XY: 0.00125 AC XY: 906 AN XY: 727120

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44714

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26126

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.0000375 AC: 2 AN: 53384

Gnomad4 NFE exome AF: 0.00160 AC: 1776 AN: 1111840

Gnomad4 Remaining exome AF: 0.000779 AC: 47 AN: 60372

GnomAD4 genome AF: 0.000743 AC: 113 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.000538 AC XY: 40 AN XY: 74338

Gnomad4 AFR AF: 0.000290 AC: 0.000289645 AN: 0.000289645

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000941 AC: 0.0000941442 AN: 0.0000941442

Gnomad4 NFE AF: 0.00146 AC: 0.00145528 AN: 0.00145528

Gnomad4 OTH AF: 0.000479 AC: 0.000478927 AN: 0.000478927

Alfa AF: 0.000445 Hom.: 0

Bravo AF: 0.000657

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000953 AC: 8

ExAC AF: 0.000413 AC: 50

EpiCase AF: 0.00120

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

TREH-related disorder Uncertain:1

Feb 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TREH c.1525A>T variant is predicted to result in premature protein termination (p.Lys509*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.097% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.065
FATHMM_MKL	Benign	0.12	N
Vest4		0.78
GERP RS		4.2
Mutation Taster		=83/117	disease causing (fs/PTC)

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

LitVar

Other links and lift over

dbSNP: rs201467126; hg19: chr11-118529634;