11-118659457-A-G

Position:

• chr11-118659457-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007180.3(TREH):​c.1345T>C​(p.Tyr449His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,604,718 control chromosomes in the GnomAD database, including 33 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (14 hom.)
• Consequence: TREH NM_007180.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.138

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042777956).
• BP6: Variant 11-118659457-A-G is Benign according to our data. Variant chr11-118659457-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 376781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00999 (1521/152248) while in subpopulation AFR AF= 0.0345 (1431/41536). AF 95% confidence interval is 0.033. There are 19 homozygotes in gnomad4. There are 693 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREH	NM_007180.3	c.1345T>C	p.Tyr449His	missense_variant	12/15	ENST00000264029.9	NP_009111.2
TREH	NM_001301065.2	c.1252T>C	p.Tyr418His	missense_variant	11/14		NP_001287994.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREH	ENST00000264029.9	c.1345T>C	p.Tyr449His	missense_variant	12/15	1	NM_007180.3	ENSP00000264029.5
TREH	ENST00000397925.2	c.1252T>C	p.Tyr418His	missense_variant	11/14	1		ENSP00000381020.2
TREH	ENST00000613915.4	n.*1122T>C		non_coding_transcript_exon_variant	10/13	2		ENSP00000477923.1
TREH	ENST00000613915.4	n.*1122T>C		3_prime_UTR_variant	10/13	2		ENSP00000477923.1

Frequencies

GnomAD3 genomes AF: 0.00998 AC: 1519 AN: 152130 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00253 AC: 596 AN: 236032 Hom.: 7 AF XY: 0.00182 AC XY: 233 AN XY: 127928

Gnomad AFR exome AF: 0.0361

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000655

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.000980 AC: 1423 AN: 1452470 Hom.: 14 Cov.: 32 AF XY: 0.000846 AC XY: 610 AN XY: 721428

Gnomad4 AFR exome AF: 0.0347

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000524

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00999 AC: 1521 AN: 152248 Hom.: 19 Cov.: 33 AF XY: 0.00931 AC XY: 693 AN XY: 74434

Gnomad4 AFR AF: 0.0345

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00218 Hom.: 9

Bravo AF: 0.0111

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0338 AC: 130

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00289 AC: 349

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 11, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.1
DANN	Benign	0.85
DEOGEN2	Benign	0.076	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.34	N;N
REVEL	Benign	0.057
Sift	Benign	0.083	T;T
Sift4G	Benign	0.075	T;T
Polyphen		0.0010	B;.
Vest4		0.11
MVP		0.11
MPC		0.037
ClinPred		0.0033	T
GERP RS		-9.0
Varity_R		0.047
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11827611; hg19: chr11-118530166;