rs369135156

Variant summary

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

The ENST00000321264.9(D2HGDH):​c.1140+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000594 in 1,613,012 control chromosomes in the GnomAD database, including 6 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00058 ( 6 hom. )

Consequence

D2HGDH
ENST00000321264.9 splice_region, intron

Scores

2
Splicing: ADA: 0.0003680
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -1.81
Variant links:
Genes affected
D2HGDH (HGNC:28358): (D-2-hydroxyglutarate dehydrogenase) This gene encodes D-2hydroxyglutarate dehydrogenase, a mitochondrial enzyme belonging to the FAD-binding oxidoreductase/transferase type 4 family. This enzyme, which is most active in liver and kidney but also active in heart and brain, converts D-2-hydroxyglutarate to 2-ketoglutarate. Mutations in this gene are present in D-2-hydroxyglutaric aciduria, a rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. [provided by RefSeq, Jul 2008]

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 (BayesDel_noAF=-0.85).
BP6
Variant 2-241751396-G-A is Benign according to our data. Variant chr2-241751396-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210813.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000709 (108/152316) while in subpopulation AMR AF= 0.00216 (33/15304). AF 95% confidence interval is 0.00158. There are 0 homozygotes in gnomad4. There are 59 alleles in male gnomad4 subpopulation. Median coverage is 33. 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
D2HGDHNM_152783.5 linkuse as main transcriptc.1140+8G>A splice_region_variant, intron_variant ENST00000321264.9 NP_689996.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
D2HGDHENST00000321264.9 linkuse as main transcriptc.1140+8G>A splice_region_variant, intron_variant 1 NM_152783.5 ENSP00000315351 P1Q8N465-1

Frequencies

GnomAD3 genomes
AF:
0.000703
AC:
107
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000555
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00216
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000753
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000544
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000784
AC:
196
AN:
249970
Hom.:
1
AF XY:
0.000797
AC XY:
108
AN XY:
135502
show subpopulations
Gnomad AFR exome
AF:
0.000496
Gnomad AMR exome
AF:
0.00223
Gnomad ASJ exome
AF:
0.00109
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000164
Gnomad FIN exome
AF:
0.000650
Gnomad NFE exome
AF:
0.000603
Gnomad OTH exome
AF:
0.00213
GnomAD4 exome
AF:
0.000582
AC:
850
AN:
1460696
Hom.:
6
Cov.:
33
AF XY:
0.000579
AC XY:
421
AN XY:
726674
show subpopulations
Gnomad4 AFR exome
AF:
0.000538
Gnomad4 AMR exome
AF:
0.00244
Gnomad4 ASJ exome
AF:
0.00103
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000244
Gnomad4 FIN exome
AF:
0.000399
Gnomad4 NFE exome
AF:
0.000487
Gnomad4 OTH exome
AF:
0.000994
GnomAD4 genome
AF:
0.000709
AC:
108
AN:
152316
Hom.:
0
Cov.:
33
AF XY:
0.000792
AC XY:
59
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000553
Gnomad4 AMR
AF:
0.00216
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.000753
Gnomad4 NFE
AF:
0.000544
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000458
Hom.:
1
Bravo
AF:
0.00104

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

D-2-hydroxyglutaric aciduria 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -
not provided Uncertain:1Benign:1
Uncertain significance, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 24, 2016- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2022- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 09, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
0.16
DANN
Benign
0.65
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00037
dbscSNV1_RF
Benign
0.036
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.

Other links and lift over

dbSNP: rs369135156; hg19: chr2-242690811; API