chr14-50265380-T-C

Position:

chr14-50265380-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000267436.9(L2HGDH):c.1174A>G(p.Ile392Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,611,802 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I392T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 6 hom. )

Consequence

L2HGDH
ENST00000267436.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.14

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011918634).

BP6

Variant 14-50265380-T-C is Benign according to our data. Variant chr14-50265380-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435698.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000164 (25/152298) while in subpopulation EAS AF= 0.00482 (25/5184). AF 95% confidence interval is 0.00335. There are 1 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L2HGDH	NM_024884.3 linkuse as main transcript	c.1174A>G	p.Ile392Val	missense_variant	9/10	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.1174A>G	p.Ile392Val	missense_variant	9/10	1	NM_024884.3	ENSP00000267436	P1	Q9H9P8-1
L2HGDH	ENST00000261699.8 linkuse as main transcript	c.1174A>G	p.Ile392Val	missense_variant	9/10	1		ENSP00000261699
L2HGDH	ENST00000421284.7 linkuse as main transcript	c.1174A>G	p.Ile392Val	missense_variant	9/11	2		ENSP00000405559	P1	Q9H9P8-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00481

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000279

AC:

AN:

251252

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000210

AC:

306

AN:

1459504

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

150

AN XY:

726272

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00749

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000995

GnomAD4 genome

AF:

0.000164

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00482

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.000305

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 22, 2017

- -

L-2-hydroxyglutaric aciduria

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2022

- -

L2HGDH-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 02, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.099

T;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.0080

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.33

.;N;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.64

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.44

T;T;T

Sift4G

Benign

0.61

T;T;T

Polyphen

0.22

B;B;B

Vest4

0.13

MutPred

0.64

Gain of catalytic residue at D396 (P = 0.057);Gain of catalytic residue at D396 (P = 0.057);Gain of catalytic residue at D396 (P = 0.057);

MVP

0.58

MPC

0.19

ClinPred

0.078

GERP RS

5.2

Varity_R

0.038

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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