dbSNP rs767524925: L2HGDH:c.409-4G>T (chr14-50294250-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_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

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 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

L2HGDH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
L2HGDH	NM_024884.3	MANE Select	c.409-4G>T	splice_region intron	N/A	NP_079160.1
L2HGDH	NM_001425212.1		c.409-4G>T	splice_region intron	N/A	NP_001412141.1
L2HGDH	NM_001425213.1		c.298-4G>T	splice_region intron	N/A	NP_001412142.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
L2HGDH	ENST00000267436.9	TSL:1 MANE Select	c.409-4G>T	splice_region intron	N/A	ENSP00000267436.4
L2HGDH	ENST00000261699.8	TSL:1	c.409-4G>T	splice_region intron	N/A	ENSP00000261699.4
L2HGDH	ENST00000555423.5	TSL:1	c.409-4G>T	splice_region intron	N/A	ENSP00000450494.1

Frequencies

GnomAD3 genomes

AF:

0.000198

AC:

AN:

136194

Hom.:

Cov.:

show subpopulations

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

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 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

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

African (AFR)

AF:

0.00201

AC:

AN:

24324

American (AMR)

AF:

0.00335

AC:

106

AN:

31628

Ashkenazi Jewish (ASJ)

AF:

0.000900

AC:

AN:

18886

East Asian (EAS)

AF:

0.0000690

AC:

AN:

28982

South Asian (SAS)

AF:

0.000976

AC:

AN:

64546

European-Finnish (FIN)

AF:

0.000388

AC:

AN:

38620

Middle Eastern (MID)

AF:

0.000661

AC:

AN:

4540

European-Non Finnish (NFE)

AF:

0.000230

AC:

190

AN:

826400

Other (OTH)

AF:

0.000564

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.265

Heterozygous variant carriers

102

152

203

254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

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

African (AFR)

AF:

0.000189

AC:

AN:

36994

American (AMR)

AF:

0.000148

AC:

AN:

13526

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3266

East Asian (EAS)

AF:

0.00

AC:

AN:

4816

South Asian (SAS)

AF:

0.00

AC:

AN:

4300

European-Finnish (FIN)

AF:

0.00184

AC:

AN:

7590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.0000796

AC:

AN:

62784

Other (OTH)

AF:

0.00

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.262

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00107

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

L-2-hydroxyglutaric aciduria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.76

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over