rs151305613

chr14-50294145-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 2P and 15B. PM2 BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_024884.3(L2HGDH):c.510G>A(p.Glu170=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,613,838 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: L2HGDH NM_024884.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0870

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 Benign. Variant got -13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 14-50294145-C-T is Benign according to our data. Variant chr14-50294145-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 586108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50294145-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.087 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00101 (153/152066) while in subpopulation AFR AF= 0.00335 (139/41488). AF 95% confidence interval is 0.0029. There are 0 homozygotes in gnomad4. There are 80 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L2HGDH	NM_024884.3	c.510G>A	p.Glu170=	synonymous_variant	4/10	ENST00000267436.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L2HGDH	ENST00000267436.9	c.510G>A	p.Glu170=	synonymous_variant	4/10	1	NM_024884.3	P1

Frequencies

GnomAD3 genomes AF: 0.000974 AC: 148 AN: 151948 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000314 AC: 79 AN: 251402 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135876

Gnomad AFR exome AF: 0.00301

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000142 AC: 208 AN: 1461772 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 98 AN XY: 727192

Gnomad4 AFR exome AF: 0.00352

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00101 AC: 153 AN: 152066 Hom.: 0 Cov.: 32 AF XY: 0.00108 AC XY: 80 AN XY: 74330

Gnomad4 AFR AF: 0.00335

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000444 Hom.: 0

Bravo AF: 0.00114

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

L-2-hydroxyglutaric aciduria Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

L2HGDH-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	5.4
Dann	Benign	0.46

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: rs151305613; hg19: chr14-50760863;