14-50312014-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_024884.3(L2HGDH):c.137C>T(p.Thr46Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,563,862 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T46T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

L2HGDH
NM_024884.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.56

Publications

1 publications found

Variant links:

Genes affected

L2HGDH (HGNC:20499): (L-2-hydroxyglutarate dehydrogenase) This gene encodes L-2-hydroxyglutarate dehydrogenase, a FAD-dependent enzyme that oxidizes L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause L-2-hydroxyglutaric aciduria, a rare autosomal recessive neurometabolic disorder resulting in moderate to severe cognitive disability. [provided by RefSeq, Jul 2008]

L2HGDH links:

DMAC2L (HGNC:18799): (distal membrane arm assembly component 2 like) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. This gene encodes the subunit s, also known as factor B, of the proton channel. This subunit is necessary for the energy transduction activity of the ATP synthase complexes. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

DMAC2L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071794093).

BP6

Variant 14-50312014-G-A is Benign according to our data. Variant chr14-50312014-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 435697.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 = 0.00141 (214/152306) while in subpopulation AFR AF = 0.00464 (193/41574). AF 95% confidence interval is 0.00411. There are 1 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L2HGDH	NM_024884.3 link	c.137C>T	p.Thr46Ile	missense_variant	Exon 1 of 10	ENST00000267436.9	NP_079160.1	Q9H9P8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9 link	c.137C>T	p.Thr46Ile	missense_variant	Exon 1 of 10	1	NM_024884.3	ENSP00000267436.4		Q9H9P8-1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

214

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00466

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

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:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000387

AC:

AN:

165552

AF XY:

0.000310

show subpopulations

Gnomad AFR exome

AF:

0.00495

Gnomad AMR exome

AF:

0.000449

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000757

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000196

AC:

277

AN:

1411556

Hom.:

Cov.:

AF XY:

0.000185

AC XY:

129

AN XY:

698248

show subpopulations

African (AFR)

AF:

0.00560

AC:

182

AN:

32526

American (AMR)

AF:

0.000449

AC:

AN:

37832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25312

East Asian (EAS)

AF:

0.00

AC:

AN:

37394

South Asian (SAS)

AF:

0.0000124

AC:

AN:

80948

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45574

Middle Eastern (MID)

AF:

0.00197

AC:

AN:

4568

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

1088872

Other (OTH)

AF:

0.000564

AC:

AN:

58530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152306

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00464

AC:

193

AN:

41574

American (AMR)

AF:

0.000784

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000629

Hom.:

Bravo

AF:

0.00165

ESP6500AA

AF:

0.00264

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000435

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Feb 10, 2018

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

L-2-hydroxyglutaric aciduria

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

L2HGDH-related disorder

Benign:1

Dec 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.023

T;T;T;.;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.84

T;.;T;T;T

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.0072

T;T;T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

0.69

.;N;N;.;.

PhyloP100

1.6

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.8

N;N;N;N;N

REVEL

Benign

0.17

Sift

Benign

0.11

T;T;T;T;T

Sift4G

Benign

0.16

T;T;T;T;T

Polyphen

0.0080

B;B;B;.;.

Vest4

0.40

MVP

0.70

MPC

0.23

ClinPred

0.020

GERP RS

2.6

PromoterAI

0.079

Neutral

(source)

Varity_R

0.077

gMVP

0.26

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over