rs767524925

chr14-50294250-C-Achr14-50294250-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_024884.3(L2HGDH):c.409-4G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,082,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: L2HGDH NM_024884.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009650
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.19

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 14-50294250-C-A is Benign according to our data. Variant chr14-50294250-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 466267.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000434 (470/1082226) while in subpopulation AMR AF= 0.00335 (106/31628). AF 95% confidence interval is 0.00283. There are 0 homozygotes in gnomad4_exome. There are 241 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L2HGDH	NM_024884.3	c.409-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000267436.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L2HGDH	ENST00000267436.9	c.409-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_024884.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 27 AN: 136194 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00184

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000796

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00163 AC: 153 AN: 94122 Hom.: 0 AF XY: 0.00177 AC XY: 88 AN XY: 49840

Gnomad AFR exome AF: 0.000429

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00166

Gnomad EAS exome AF: 0.000887

Gnomad SAS exome AF: 0.00325

Gnomad FIN exome AF: 0.000686

Gnomad NFE exome AF: 0.00174

Gnomad OTH exome AF: 0.00387

GnomAD4 exome AF: 0.000434 AC: 470 AN: 1082226 Hom.: 0 Cov.: 34 AF XY: 0.000446 AC XY: 241 AN XY: 539814

Gnomad4 AFR exome AF: 0.00201

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.000900

Gnomad4 EAS exome AF: 0.0000690

Gnomad4 SAS exome AF: 0.000976

Gnomad4 FIN exome AF: 0.000388

Gnomad4 NFE exome AF: 0.000230

Gnomad4 OTH exome AF: 0.000564

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000205 AC: 28 AN: 136264 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 15 AN XY: 65456

Gnomad4 AFR AF: 0.000189

Gnomad4 AMR AF: 0.000148

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00184

Gnomad4 NFE AF: 0.0000796

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00107 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

L-2-hydroxyglutaric aciduria Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	0.76
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000096
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.12		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: rs767524925; hg19: chr14-50760968;