14-50294195-C-T

Variant names:

• chr14-50294195-C-T
• NM_024884.3:c.460G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024884.3(L2HGDH):​c.460G>A​(p.Glu154Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3684214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L2HGDH	NM_024884.3	c.460G>A	p.Glu154Lys	missense_variant	Exon 4 of 10	ENST00000267436.9	NP_079160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9	c.460G>A	p.Glu154Lys	missense_variant	Exon 4 of 10	1	NM_024884.3	ENSP00000267436.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;T;.;T
Eigen	Benign	0.044
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.37	T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.4	.;L;L;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.4	N;D;D;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.24	T;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.59	P;B;B;.;.
Vest4		0.29
MutPred		0.57		Gain of MoRF binding (P = 0.0211);Gain of MoRF binding (P = 0.0211);Gain of MoRF binding (P = 0.0211);Gain of MoRF binding (P = 0.0211);Gain of MoRF binding (P = 0.0211);
MVP		0.75
MPC		0.29
ClinPred		0.89	D
GERP RS		4.3
Varity_R		0.52
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-50760913;