chr14-50283859-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024884.3(L2HGDH):​c.703+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,609,744 control chromosomes in the GnomAD database, including 246,774 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20202 hom., cov: 31)
Exomes 𝑓: 0.56 ( 226572 hom. )

Consequence

L2HGDH
NM_024884.3 intron

Scores

2

Clinical Significance

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

Conservation

PhyloP100: 0.0670

Publications

16 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 Gene-Disease associations (from GenCC):
  • L-2-hydroxyglutaric aciduria
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
  • mitochondrial disease
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 14-50283859-A-G is Benign according to our data. Variant chr14-50283859-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 158801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
L2HGDHNM_024884.3 linkc.703+12T>C intron_variant Intron 5 of 9 ENST00000267436.9 NP_079160.1 Q9H9P8-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
L2HGDHENST00000267436.9 linkc.703+12T>C intron_variant Intron 5 of 9 1 NM_024884.3 ENSP00000267436.4 Q9H9P8-1

Frequencies

GnomAD3 genomes
AF:
0.509
AC:
77264
AN:
151846
Hom.:
20171
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.397
Gnomad AMI
AF:
0.509
Gnomad AMR
AF:
0.447
Gnomad ASJ
AF:
0.507
Gnomad EAS
AF:
0.651
Gnomad SAS
AF:
0.531
Gnomad FIN
AF:
0.584
Gnomad MID
AF:
0.510
Gnomad NFE
AF:
0.567
Gnomad OTH
AF:
0.511
GnomAD2 exomes
AF:
0.538
AC:
135080
AN:
251222
AF XY:
0.543
show subpopulations
Gnomad AFR exome
AF:
0.394
Gnomad AMR exome
AF:
0.441
Gnomad ASJ exome
AF:
0.496
Gnomad EAS exome
AF:
0.653
Gnomad FIN exome
AF:
0.582
Gnomad NFE exome
AF:
0.564
Gnomad OTH exome
AF:
0.531
GnomAD4 exome
AF:
0.555
AC:
809721
AN:
1457778
Hom.:
226572
Cov.:
32
AF XY:
0.555
AC XY:
402762
AN XY:
725462
show subpopulations
African (AFR)
AF:
0.390
AC:
13037
AN:
33404
American (AMR)
AF:
0.444
AC:
19869
AN:
44702
Ashkenazi Jewish (ASJ)
AF:
0.495
AC:
12906
AN:
26094
East Asian (EAS)
AF:
0.636
AC:
25244
AN:
39664
South Asian (SAS)
AF:
0.542
AC:
46669
AN:
86132
European-Finnish (FIN)
AF:
0.583
AC:
31105
AN:
53356
Middle Eastern (MID)
AF:
0.455
AC:
2620
AN:
5752
European-Non Finnish (NFE)
AF:
0.564
AC:
625377
AN:
1108440
Other (OTH)
AF:
0.546
AC:
32894
AN:
60234
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
15949
31897
47846
63794
79743
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
17348
34696
52044
69392
86740
<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:
0.509
AC:
77351
AN:
151966
Hom.:
20202
Cov.:
31
AF XY:
0.508
AC XY:
37763
AN XY:
74276
show subpopulations
African (AFR)
AF:
0.397
AC:
16461
AN:
41416
American (AMR)
AF:
0.448
AC:
6839
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.507
AC:
1759
AN:
3470
East Asian (EAS)
AF:
0.652
AC:
3365
AN:
5164
South Asian (SAS)
AF:
0.532
AC:
2566
AN:
4824
European-Finnish (FIN)
AF:
0.584
AC:
6158
AN:
10552
Middle Eastern (MID)
AF:
0.507
AC:
148
AN:
292
European-Non Finnish (NFE)
AF:
0.567
AC:
38514
AN:
67962
Other (OTH)
AF:
0.511
AC:
1080
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
1887
3774
5662
7549
9436
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
692
1384
2076
2768
3460
<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:
0.535
Hom.:
6336
Bravo
AF:
0.493
Asia WGS
AF:
0.524
AC:
1820
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

L-2-hydroxyglutaric aciduria Benign:2
Aug 19, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Oct 31, 2013
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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
BayesDel_noAF
Benign
-0.88
CADD
Benign
2.3
DANN
Benign
0.42
PhyloP100
0.067
Mutation Taster
=99/1
polymorphism (auto)

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

Other links and lift over

dbSNP: rs12433038; hg19: chr14-50750577; API