rs767524925

Variant names:

• chr14-50294250-C-A
• rs767524925
• NM_024884.3:c.409-4G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-50294250-C-A
• chr14-50294250-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_024884.3(L2HGDH):​c.409-4G>T variant causes a splice region, 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. 3/3 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, intron
• Scores: Splicing: ADA: 0.00009650
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.19
• 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_benign. The variant received -6 ACMG points.

• 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 VariationId is 466267.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L2HGDH	NM_024884.3	c.409-4G>T		splice_region_variant, intron_variant	Intron 3 of 9	ENST00000267436.9	NP_079160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9	c.409-4G>T		splice_region_variant, intron_variant	Intron 3 of 9	1	NM_024884.3	ENSP00000267436.4

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 27 AN: 136194 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00163 AC: 153 AN: 94122 AF XY: 0.00177

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00201 AC: 49 AN: 24324

American (AMR) AF: 0.00335 AC: 106 AN: 31628

Ashkenazi Jewish (ASJ) AF: 0.000900 AC: 17 AN: 18886

East Asian (EAS) AF: 0.0000690 AC: 2 AN: 28982

South Asian (SAS) AF: 0.000976 AC: 63 AN: 64546

European-Finnish (FIN) AF: 0.000388 AC: 15 AN: 38620

Middle Eastern (MID) AF: 0.000661 AC: 3 AN: 4540

European-Non Finnish (NFE) AF: 0.000230 AC: 190 AN: 826400

Other (OTH) AF: 0.000564 AC: 25 AN: 44300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000189 AC: 7 AN: 36994

American (AMR) AF: 0.000148 AC: 2 AN: 13526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3266

East Asian (EAS) AF: 0.00 AC: 0 AN: 4816

South Asian (SAS) AF: 0.00 AC: 0 AN: 4300

European-Finnish (FIN) AF: 0.00184 AC: 14 AN: 7590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.0000796 AC: 5 AN: 62784

Other (OTH) AF: 0.00 AC: 0 AN: 1862

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.76
DANN	Benign	0.64
PhyloP100		-2.2

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

Other links and lift over

dbSNP: rs767524925; hg19: chr14-50760968;