Genetic Variant OGDHL:p.Ala940Thr (chr10-49736114-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

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

The NM_018245.3(OGDHL):c.2818G>A(p.Ala940Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00129 in 1,612,092 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0047 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00093 ( 6 hom. )

Consequence

OGDHL
NM_018245.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.92

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:

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=0.010488629).

BP6

Variant 10-49736114-C-T is Benign according to our data. Variant chr10-49736114-C-T is described in ClinVar as [Benign]. Clinvar id is 3043968.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00469 (715/152298) while in subpopulation AFR AF= 0.0143 (593/41566). AF 95% confidence interval is 0.0133. There are 7 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OGDHL	NM_018245.3 link	c.2818G>A	p.Ala940Thr	missense_variant	Exon 22 of 23	ENST00000374103.9	NP_060715.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OGDHL	ENST00000374103.9 link	c.2818G>A	p.Ala940Thr	missense_variant	Exon 22 of 23	1	NM_018245.3	ENSP00000363216.4	Q9ULD0-1
OGDHL	ENST00000419399.4 link	c.2647G>A	p.Ala883Thr	missense_variant	Exon 21 of 22	2		ENSP00000401356.1	Q9ULD0-2
OGDHL	ENST00000432695.2 link	c.2191G>A	p.Ala731Thr	missense_variant	Exon 20 of 21	2		ENSP00000390240.1	Q9ULD0-3
OGDHL	ENST00000490844.1 link	n.1854G>A		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.00470

AC:

715

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00146

AC:

363

AN:

248424

Hom.:

AF XY:

0.00115

AC XY:

154

AN XY:

134184

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.000811

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.000527

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000931

AC:

1359

AN:

1459794

Hom.:

Cov.:

AF XY:

0.000865

AC XY:

628

AN XY:

726120

show subpopulations

Gnomad4 AFR exome

AF:

0.0143

Gnomad4 AMR exome

AF:

0.00182

Gnomad4 ASJ exome

AF:

0.00104

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.0000938

Gnomad4 NFE exome

AF:

0.000577

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.00469

AC:

715

AN:

152298

Hom.:

Cov.:

AF XY:

0.00411

AC XY:

306

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0143

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000779

Gnomad4 OTH

AF:

0.00522

Alfa

AF:

0.00201

Hom.:

Bravo

AF:

0.00538

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0154

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00166

AC:

202

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

OGDHL-related disorder

Benign:1

Mar 04, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

0.099

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

T;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.090

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.92

L;.;.

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.44

N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.011

D;D;D

Polyphen

0.0030

B;B;B

Vest4

0.31

MVP

0.35

MPC

0.17

ClinPred

0.023

GERP RS

3.7

Varity_R

0.23

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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