10-49739779-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BP4_Strong BS2

The NM_018245.3(OGDHL):c.2201T>C(p.Phe734Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00594 in 1,614,084 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (66 hom.)
• Consequence: OGDHL NM_018245.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.022460788).
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OGDHL	NM_018245.3	c.2201T>C	p.Phe734Ser	missense_variant	17/23	ENST00000374103.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OGDHL	ENST00000374103.9	c.2201T>C	p.Phe734Ser	missense_variant	17/23	1	NM_018245.3	P1
OGDHL	ENST00000419399.4	c.2030T>C	p.Phe677Ser	missense_variant	16/22	2
OGDHL	ENST00000432695.2	c.1574T>C	p.Phe525Ser	missense_variant	15/21	2

Frequencies

GnomAD3 genomes AF: 0.00626 AC: 953 AN: 152166 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0421

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00716 AC: 1799 AN: 251318 Hom.: 26 AF XY: 0.00715 AC XY: 971 AN XY: 135822

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.0360

Gnomad NFE exome AF: 0.00641

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.00591 AC: 8636 AN: 1461800 Hom.: 66 Cov.: 31 AF XY: 0.00578 AC XY: 4201 AN XY: 727210

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00470

Gnomad4 ASJ exome AF: 0.00214

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.00534

Gnomad4 OTH exome AF: 0.00541

GnomAD4 genome AF: 0.00626 AC: 953 AN: 152284 Hom.: 9 Cov.: 33 AF XY: 0.00798 AC XY: 594 AN XY: 74472

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0421

Gnomad4 NFE AF: 0.00550

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00417 Hom.: 1

Bravo AF: 0.00350

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00648 AC: 787

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2017

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

OGDHL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2019

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

OGDHL: PP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	4.4	H;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.99
MVP		0.97
MPC		0.95
ClinPred		0.13	T
GERP RS		4.5
Varity_R		0.98
gMVP		0.88

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

Other links and lift over

dbSNP: rs143105288; hg19: chr10-50947825; COSMIC: COSV100934128; COSMIC: COSV100934128;