Variant rs767524925 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

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. 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, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00009650

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.19

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
L2HGDH	NM_024884.3 linkuse as main transcript	c.409-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000267436.9	NP_079160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L2HGDH	ENST00000267436.9 linkuse as main transcript	c.409-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_024884.3	ENSP00000267436	P1	Q9H9P8-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

136194

Hom.:

Cov.:

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.:

AF XY:

0.00177

AC XY:

AN XY:

49840

show subpopulations

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.:

Cov.:

AF XY:

0.000446

AC XY:

241

AN XY:

539814

show subpopulations

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:

AN:

136264

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

65456

show subpopulations

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.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

L-2-hydroxyglutaric aciduria

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over