14-50269162-C-A

Variant names:

• chr14-50269162-C-A
• rs786200870
• NM_024884.3:c.906+1G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_024884.3(L2HGDH):​c.906+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: L2HGDH NM_024884.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.59
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.12068965 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.6, offset of 4, new splice context is: tagGTaatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-50269162-C-A is Pathogenic according to our data. Variant chr14-50269162-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1609.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	NM_024884.3	MANE Select	c.906+1G>T		splice_donor intron	N/A	NP_079160.1
	L2HGDH	NM_001425212.1		c.906+1G>T		splice_donor intron	N/A	NP_001412141.1
	L2HGDH	NM_001425213.1		c.795+1G>T		splice_donor intron	N/A	NP_001412142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L2HGDH	ENST00000267436.9	TSL:1 MANE Select	c.906+1G>T		splice_donor intron	N/A	ENSP00000267436.4
	L2HGDH	ENST00000261699.8	TSL:1	c.906+1G>T		splice_donor intron	N/A	ENSP00000261699.4
	L2HGDH	ENST00000421284.7	TSL:2	c.906+1G>T		splice_donor intron	N/A	ENSP00000405559.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1306820 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 648912

African (AFR) AF: 0.00 AC: 0 AN: 28988

American (AMR) AF: 0.00 AC: 0 AN: 40136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20590

East Asian (EAS) AF: 0.00 AC: 0 AN: 26690

South Asian (SAS) AF: 0.00 AC: 0 AN: 84710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4982

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1008028

Other (OTH) AF: 0.00 AC: 0 AN: 50596

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

L-2-hydroxyglutaric aciduria Pathogenic:1

Nov 15, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.6
GERP RS		5.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -3
DS_DL_spliceai		0.98		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786200870; hg19: chr14-50735880;