rs2276065

Positions:

• chr11-118659902-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -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 id 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/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: no assertion criteria provided

Submissions by phenotype

TREH-related disorder Benign:1

Benign, no assertion criteria provided

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;