rs2276065

chr11-118659902-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3328 hom., cov: 32)
  • Exomes 𝑓: 0.23 (38820 hom.)
• Consequence: TREH NM_007180.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.897

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

Verdict is Benign. Variant got -14 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 id is 3060563.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
TREH	NM_007180.3	c.1165A>G	p.Thr389Ala	missense_variant	11/15	ENST00000264029.9
TREH	NM_001301065.2	c.1072A>G	p.Thr358Ala	missense_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TREH	ENST00000264029.9	c.1165A>G	p.Thr389Ala	missense_variant	11/15	1	NM_007180.3	P1
TREH	ENST00000397925.2	c.1072A>G	p.Thr358Ala	missense_variant	10/14	1
TREH	ENST00000531295.5	n.1428A>G		non_coding_transcript_exon_variant	10/10	5
TREH	ENST00000613915.4	c.*942A>G		3_prime_UTR_variant, NMD_transcript_variant	9/13	2

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30699 AN: 152062 Hom.: 3326 Cov.: 32

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

GnomAD3 exomes AF: 0.235 AC: 36939 AN: 157018 Hom.: 4686 AF XY: 0.245 AC XY: 20358 AN XY: 83030

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 SAS exome AF: 0.341

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.: 35 AF XY: 0.236 AC XY: 162566 AN XY: 690246

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.338

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.230

Gnomad4 OTH exome AF: 0.232

GnomAD4 genome AF: 0.202 AC: 30709 AN: 152180 Hom.: 3328 Cov.: 32 AF XY: 0.205 AC XY: 15268 AN XY: 74412

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.238

Gnomad4 ASJ AF: 0.202

Gnomad4 EAS AF: 0.243

Gnomad4 SAS AF: 0.358

Gnomad4 FIN AF: 0.219

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.197

Alfa AF: 0.218 Hom.: 1446

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: criteria provided, single submitter

Submissions by phenotype

TREH-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.36
Dann	Benign	0.38
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00039	N
LIST_S2	Benign	0.087	T;T
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.35	T
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	T
GERP RS		3.8
Varity_R		0.047
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs2276065; hg19: chr11-118530611; COSMIC: COSV50620117; COSMIC: COSV50620117;