Genetic Variant NM_018245.3:c.2333C>G (chr10-49738249-G-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_018245.3(OGDHL):c.2333C>G(p.Ser778Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S778L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

OGDHL
NM_018245.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.89

Variant links:

Genes affected

OGDHL (HGNC:25590): (oxoglutarate dehydrogenase L) The protein encoded by this gene is similar to oxoglutarate dehydrogenase (OGDH) of the OGDH complex, which degrades glucose and glutamate. This gene encodes several isoforms, including some that appear to localize to mitochondria. The encoded protein down-regulates the AKT signaling cascade and can suppress the growth of cervical cancer cells. [provided by RefSeq, Dec 2016]

OGDHL links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-49738249-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OGDHL	NM_018245.3 link	c.2333C>G	p.Ser778Trp	missense_variant	Exon 18 of 23	ENST00000374103.9	NP_060715.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OGDHL	ENST00000374103.9 link	c.2333C>G	p.Ser778Trp	missense_variant	Exon 18 of 23	1	NM_018245.3	ENSP00000363216.4	Q9ULD0-1
OGDHL	ENST00000419399.4 link	c.2162C>G	p.Ser721Trp	missense_variant	Exon 17 of 22	2		ENSP00000401356.1	Q9ULD0-2
OGDHL	ENST00000432695.2 link	c.1706C>G	p.Ser569Trp	missense_variant	Exon 16 of 21	2		ENSP00000390240.1	Q9ULD0-3
OGDHL	ENST00000490844.1 link	n.1251C>G		non_coding_transcript_exon_variant	Exon 1 of 5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251368

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460728

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726700

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

H;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.2

D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.91

MutPred

0.73

Gain of catalytic residue at S778 (P = 0.0022);.;.;

MVP

0.96

MPC

0.84

ClinPred

1.0

GERP RS

4.5

Varity_R

0.94

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over