chr14-50283859-A-G

Variant names:

• chr14-50283859-A-G
• rs12433038
• NM_024884.3:c.703+12T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0670
• Publications: 16 publications found

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

ACMG classification

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
L2HGDH	NM_024884.3	c.703+12T>C		intron_variant	Intron 5 of 9	ENST00000267436.9	NP_079160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9	c.703+12T>C		intron_variant	Intron 5 of 9	1	NM_024884.3	ENSP00000267436.4

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77264 AN: 151846 Hom.: 20171 Cov.: 31

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

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

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

GnomAD4 genome AF: 0.509 AC: 77351 AN: 151966 Hom.: 20202 Cov.: 31 AF XY: 0.508 AC XY: 37763 AN XY: 74276

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

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

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

Other links and lift over

dbSNP: rs12433038; hg19: chr14-50750577;