rs35710558

Variant names:

• chr14-50312052-C-A
• rs35710558
• NM_024884.3:c.99G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024884.3(L2HGDH):​c.99G>T​(p.Arg33Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,590,234 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (26 hom.)
• Consequence: L2HGDH NM_024884.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.21
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021855533).
• BP6: Variant 14-50312052-C-A is Benign according to our data. Variant chr14-50312052-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158803.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 = 0.00955 (1454/152300) while in subpopulation AFR AF = 0.0331 (1376/41562). AF 95% confidence interval is 0.0317. There are 24 homozygotes in GnomAd4. There are 675 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

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.99G>T	p.Arg33Ser	missense	Exon 1 of 10	NP_079160.1	Q9H9P8-1
	L2HGDH	NM_001425212.1		c.99G>T	p.Arg33Ser	missense	Exon 1 of 11	NP_001412141.1	Q9H9P8-1
	L2HGDH	NM_001425213.1		c.-156G>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.99G>T	p.Arg33Ser	missense	Exon 1 of 10	ENSP00000267436.4	Q9H9P8-1
	L2HGDH	ENST00000261699.8	TSL:1	c.99G>T	p.Arg33Ser	missense	Exon 1 of 10	ENSP00000261699.4	C9JVN9
	L2HGDH	ENST00000555423.5	TSL:1	c.99G>T	p.Arg33Ser	missense	Exon 1 of 6	ENSP00000450494.1	G3V272

Frequencies

GnomAD3 genomes AF: 0.00951 AC: 1447 AN: 152182 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00259 AC: 524 AN: 202302 AF XY: 0.00202

Gnomad AFR exome AF: 0.0374

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.00252

GnomAD4 exome AF: 0.00101 AC: 1448 AN: 1437934 Hom.: 26 Cov.: 31 AF XY: 0.000862 AC XY: 615 AN XY: 713562

African (AFR) AF: 0.0335 AC: 1110 AN: 33112

American (AMR) AF: 0.00197 AC: 81 AN: 41058

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25664

East Asian (EAS) AF: 0.00 AC: 0 AN: 38728

South Asian (SAS) AF: 0.0000839 AC: 7 AN: 83398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48750

Middle Eastern (MID) AF: 0.00389 AC: 21 AN: 5400

European-Non Finnish (NFE) AF: 0.0000735 AC: 81 AN: 1102292

Other (OTH) AF: 0.00247 AC: 147 AN: 59532

GnomAD4 genome AF: 0.00955 AC: 1454 AN: 152300 Hom.: 24 Cov.: 32 AF XY: 0.00906 AC XY: 675 AN XY: 74474

African (AFR) AF: 0.0331 AC: 1376 AN: 41562

American (AMR) AF: 0.00398 AC: 61 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00179 Hom.: 8

Bravo AF: 0.0108

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0265 AC: 116

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00266 AC: 319

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	5.5
DANN	Benign	0.84
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.55	N
PhyloP100		-1.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.10
Sift	Benign	0.77	T
Sift4G	Benign	0.64	T
Polyphen		0.051	B
Vest4		0.26
MutPred		0.39		Gain of catalytic residue at L37 (P = 0)
MVP		0.61
MPC		0.24
ClinPred		0.0054	T
GERP RS		0.035
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.31
Mutation Taster		=100/0	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: rs35710558; hg19: chr14-50778770;