rs761645660

Variant names:

• chr14-50294176-C-T
• rs761645660
• NM_024884.3:c.479G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001425215.1(L2HGDH):​c.-147G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000446 in 1,613,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: L2HGDH NM_001425215.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.06
• Publications: 0 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.395164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425215.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	NM_024884.3	MANE Select	c.479G>A	p.Gly160Asp	missense	Exon 4 of 10	NP_079160.1	Q9H9P8-1
	L2HGDH	NM_001425215.1		c.-147G>A		5_prime_UTR_premature_start_codon_gain	Exon 5 of 12	NP_001412144.1
	L2HGDH	NM_001425216.1		c.-68G>A		5_prime_UTR_premature_start_codon_gain	Exon 5 of 12	NP_001412145.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	ENST00000267436.9	TSL:1 MANE Select	c.479G>A	p.Gly160Asp	missense	Exon 4 of 10	ENSP00000267436.4	Q9H9P8-1
	L2HGDH	ENST00000261699.8	TSL:1	c.479G>A	p.Gly160Asp	missense	Exon 4 of 10	ENSP00000261699.4	C9JVN9
	L2HGDH	ENST00000555423.5	TSL:1	c.479G>A	p.Gly160Asp	missense	Exon 4 of 6	ENSP00000450494.1	G3V272

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251378 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1461742 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111944

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151906 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74190

African (AFR) AF: 0.00 AC: 0 AN: 41340

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000225 Hom.: 0

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	L-2-hydroxyglutaric aciduria (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.40	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.49
Sift	Benign	0.10	T
Sift4G	Benign	0.13	T
Polyphen		0.40	B
Vest4		0.29
MutPred		0.78		Gain of relative solvent accessibility (P = 0.0289)
MVP		0.89
MPC		0.30
ClinPred		0.22	T
GERP RS		4.3
Varity_R		0.23
gMVP		0.59
Mutation Taster		=63/37	polymorphism

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: rs761645660; hg19: chr14-50760894;