NM_024884.3:c.137C>T

Variant names:

• chr14-50312014-G-A
• rs201806251
• NM_024884.3:c.137C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_024884.3(L2HGDH):​c.137C>T​(p.Thr46Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,563,862 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T46T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.56
• Publications: 1 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]

DMAC2L (HGNC:18799): (distal membrane arm assembly component 2 like) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. This gene encodes the subunit s, also known as factor B, of the proton channel. This subunit is necessary for the energy transduction activity of the ATP synthase complexes. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071794093).
• BP6: Variant 14-50312014-G-A is Benign according to our data. Variant chr14-50312014-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 435697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00141 (214/152306) while in subpopulation AFR AF = 0.00464 (193/41574). AF 95% confidence interval is 0.00411. There are 1 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024884.3. 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.137C>T	p.Thr46Ile	missense	Exon 1 of 10	NP_079160.1	Q9H9P8-1
	L2HGDH	NM_001425212.1		c.137C>T	p.Thr46Ile	missense	Exon 1 of 11	NP_001412141.1	Q9H9P8-1
	L2HGDH	NM_001425213.1		c.-118C>T		5_prime_UTR	Exon 1 of 12	NP_001412142.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	ENST00000267436.9	TSL:1 MANE Select	c.137C>T	p.Thr46Ile	missense	Exon 1 of 10	ENSP00000267436.4	Q9H9P8-1
	L2HGDH	ENST00000261699.8	TSL:1	c.137C>T	p.Thr46Ile	missense	Exon 1 of 10	ENSP00000261699.4	C9JVN9
	L2HGDH	ENST00000555423.5	TSL:1	c.137C>T	p.Thr46Ile	missense	Exon 1 of 6	ENSP00000450494.1	G3V272

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000387 AC: 64 AN: 165552 AF XY: 0.000310

Gnomad AFR exome AF: 0.00495

Gnomad AMR exome AF: 0.000449

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000757

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000196 AC: 277 AN: 1411556 Hom.: 0 Cov.: 31 AF XY: 0.000185 AC XY: 129 AN XY: 698248

African (AFR) AF: 0.00560 AC: 182 AN: 32526

American (AMR) AF: 0.000449 AC: 17 AN: 37832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25312

East Asian (EAS) AF: 0.00 AC: 0 AN: 37394

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45574

Middle Eastern (MID) AF: 0.00197 AC: 9 AN: 4568

European-Non Finnish (NFE) AF: 0.0000321 AC: 35 AN: 1088872

Other (OTH) AF: 0.000564 AC: 33 AN: 58530

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74482

African (AFR) AF: 0.00464 AC: 193 AN: 41574

American (AMR) AF: 0.000784 AC: 12 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000629 Hom.: 1

Bravo AF: 0.00165

ESP6500AA AF: 0.00264 AC: 11

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000435 AC: 51

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	L-2-hydroxyglutaric aciduria (1)
-	-	1	L2HGDH-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.0072	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.17
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Polyphen		0.0080	B
Vest4		0.40
MVP		0.70
MPC		0.23
ClinPred		0.020	T
GERP RS		2.6
PromoterAI		0.079	Neutral
Varity_R		0.077
gMVP		0.26
Mutation Taster		=80/20	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: rs201806251; hg19: chr14-50778732;