10-49736114-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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 (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00093 (6 hom.)
• Consequence: OGDHL NM_018245.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.92

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 -14 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 criteria_provided_single_submitter, 1 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 GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OGDHL	NM_018245.3	c.2818G>A	p.Ala940Thr	missense_variant	22/23	ENST00000374103.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OGDHL	ENST00000374103.9	c.2818G>A	p.Ala940Thr	missense_variant	22/23	1	NM_018245.3	P1
OGDHL	ENST00000419399.4	c.2647G>A	p.Ala883Thr	missense_variant	21/22	2
OGDHL	ENST00000432695.2	c.2191G>A	p.Ala731Thr	missense_variant	20/21	2
OGDHL	ENST00000490844.1	n.1854G>A		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 715 AN: 152180 Hom.: 7 Cov.: 33

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.: 4 AF XY: 0.00115 AC XY: 154 AN XY: 134184

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.: 6 Cov.: 34 AF XY: 0.000865 AC XY: 628 AN XY: 726120

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.: 7 Cov.: 33 AF XY: 0.00411 AC XY: 306 AN XY: 74458

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.: 1

Bravo AF: 0.00538

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00166 AC: 202

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

OGDHL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.072	T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.92	L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
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	T
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

Other links and lift over

dbSNP: rs75372646; hg19: chr10-50944160; COSMIC: COSV65102480;