rs1555328744

chr14-50267759-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024884.3(L2HGDH):c.1058T>C(p.Ile353Thr) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.704

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0370062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L2HGDH	NM_024884.3	c.1058T>C	p.Ile353Thr	missense_variant	8/10	ENST00000267436.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L2HGDH	ENST00000267436.9	c.1058T>C	p.Ile353Thr	missense_variant	8/10	1	NM_024884.3	P1
L2HGDH	ENST00000261699.8	c.1058T>C	p.Ile353Thr	missense_variant	8/10	1
L2HGDH	ENST00000421284.7	c.1058T>C	p.Ile353Thr	missense_variant	8/11	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	4.7
Dann	Benign	0.23
DEOGEN2	Benign	0.072	T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.47	T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.037	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.3	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.94	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.14
MutPred		0.45		Gain of catalytic residue at L357 (P = 0);Gain of catalytic residue at L357 (P = 0);Gain of catalytic residue at L357 (P = 0);
MVP		0.26
MPC		0.26
ClinPred		0.020	T
GERP RS		1.3
Varity_R		0.036
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs1555328744; hg19: chr14-50734477;