rs35710558

chr14-50312052-C-A

Variant summary

Our verdict is Benign. Variant got -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. 13/19 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:5
• Conservation: PhyloP100: -1.21

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:):

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 158803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50312052-C-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L2HGDH	NM_024884.3	c.99G>T	p.Arg33Ser	missense_variant	1/10	ENST00000267436.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L2HGDH	ENST00000267436.9	c.99G>T	p.Arg33Ser	missense_variant	1/10	1	NM_024884.3	P1

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

GnomAD3 exomes AF: 0.00259 AC: 524 AN: 202302 Hom.: 10 AF XY: 0.00202 AC XY: 224 AN XY: 110826

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 SAS exome AF: 0.0000368

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

Gnomad4 AFR exome AF: 0.0335

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000839

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000735

Gnomad4 OTH exome AF: 0.00247

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

Gnomad4 AFR AF: 0.0331

Gnomad4 AMR AF: 0.00398

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00116 Hom.: 4

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

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

L-2-hydroxyglutaric aciduria Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 02, 2020	- -

L2HGDH-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 25, 2017

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.77	T;.;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.20	N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.77	T;T;T;T;T
Sift4G	Benign	0.64	T;T;T;T;T
Polyphen		0.051	B;B;B;.;.
Vest4		0.26
MutPred		0.39		Gain of catalytic residue at L37 (P = 0);Gain of catalytic residue at L37 (P = 0);Gain of catalytic residue at L37 (P = 0);Gain of catalytic residue at L37 (P = 0);Gain of catalytic residue at L37 (P = 0);
MVP		0.61
MPC		0.24
ClinPred		0.0054	T
GERP RS		0.035
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.31

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: rs35710558; hg19: chr14-50778770;