14-50246961-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024884.3(L2HGDH):c.*97A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.997 in 1,466,954 control chromosomes in the GnomAD database, including 729,595 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 1.0 (75777 hom., cov: 32)
  • Exomes 𝑓: 1.0 (653818 hom.)
• Consequence: L2HGDH NM_024884.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.530

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-50246961-T-G is Benign according to our data. Variant chr14-50246961-T-G is described in ClinVar as [Benign]. Clinvar id is 1238644.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L2HGDH	NM_024884.3	c.*97A>C		3_prime_UTR_variant	10/10	ENST00000267436.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L2HGDH	ENST00000267436.9	c.*97A>C		3_prime_UTR_variant	10/10	1	NM_024884.3	P1
L2HGDH	ENST00000261699.8	c.1197-9236A>C		intron_variant		1
L2HGDH	ENST00000421284.7	c.*17+80A>C		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.998 AC: 151809 AN: 152186 Hom.: 75718 Cov.: 32

Gnomad AFR AF: 0.999

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.995

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.997

GnomAD4 exome AF: 0.997 AC: 1311134 AN: 1314650 Hom.: 653818 Cov.: 21 AF XY: 0.997 AC XY: 643084 AN XY: 644824

Gnomad4 AFR exome AF: 0.999

Gnomad4 AMR exome AF: 0.997

Gnomad4 ASJ exome AF: 0.994

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 0.996

Gnomad4 NFE exome AF: 0.997

Gnomad4 OTH exome AF: 0.998

GnomAD4 genome AF: 0.998 AC: 151927 AN: 152304 Hom.: 75777 Cov.: 32 AF XY: 0.998 AC XY: 74271 AN XY: 74454

Gnomad4 AFR AF: 0.999

Gnomad4 AMR AF: 0.996

Gnomad4 ASJ AF: 0.994

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 0.995

Gnomad4 NFE AF: 0.997

Gnomad4 OTH AF: 0.997

Alfa AF: 0.998 Hom.: 48166

Bravo AF: 0.998

Asia WGS AF: 1.00 AC: 3477 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.9
Dann	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs7143186; hg19: chr14-50713679;