14-50237660-ATGT-A

Position:

• chr14-50237660-ATGT-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PM4_Supporting BP6_Moderate BS1 BS2

The ENST00000261699.8(L2HGDH):​c.1259_1261del​(p.Asn420del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,609,136 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (11 hom.)
• Consequence: L2HGDH ENST00000261699.8 inframe_deletion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.05

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 -9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000261699.8. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 14-50237660-ATGT-A is Benign according to our data. Variant chr14-50237660-ATGT-A is described in ClinVar as [Likely_benign]. Clinvar id is 1694718.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00176 (268/152276) while in subpopulation SAS AF= 0.00435 (21/4826). AF 95% confidence interval is 0.00292. There are 0 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000261699.8	c.1259_1261del	p.Asn420del	inframe_deletion	10/10	1		ENSP00000261699

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00220 AC: 518 AN: 235274 Hom.: 2 AF XY: 0.00256 AC XY: 331 AN XY: 129070

Gnomad AFR exome AF: 0.000945

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00195

Gnomad EAS exome AF: 0.0000572

Gnomad SAS exome AF: 0.00380

Gnomad FIN exome AF: 0.00357

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00205

GnomAD4 exome AF: 0.00244 AC: 3555 AN: 1456860 Hom.: 11 AF XY: 0.00253 AC XY: 1831 AN XY: 724292

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00146

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00458

Gnomad4 FIN exome AF: 0.00345

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.00195 AC XY: 145 AN XY: 74446

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.00228

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00189 Hom.: 0

Bravo AF: 0.00155

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

L2HGDH: PM4, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs542783832; hg19: chr14-50704378;