12-122978864-G-A

Position:

• chr12-122978864-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001304833.2(OGFOD2):​c.643G>A​(p.Asp215Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,611,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: OGFOD2 NM_001304833.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

OGFOD2 (HGNC:25823): (2-oxoglutarate and iron dependent oxygenase domain containing 2) Predicted to enable several functions, including L-ascorbic acid binding activity; dioxygenase activity; and iron ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ABCB9 (HGNC:50): (ATP binding cassette subfamily B member 9) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This family member functions in the translocation of peptides from the cytosol into the lysosomal lumen. Alternative splicing of this gene results in distinct isoforms which are likely to have different substrate specificities. [provided by RefSeq, Jul 2011]

OGFOD2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024413407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OGFOD2	NM_001304833.2	c.643G>A	p.Asp215Asn	missense_variant	6/7	ENST00000228922.12	NP_001291762.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OGFOD2	ENST00000228922.12	c.643G>A	p.Asp215Asn	missense_variant	6/7	1	NM_001304833.2	ENSP00000228922.7

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000664 AC: 159 AN: 239418 Hom.: 0 AF XY: 0.000676 AC XY: 89 AN XY: 131580

Gnomad AFR exome AF: 0.000349

Gnomad AMR exome AF: 0.000472

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.000830

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.000689

GnomAD4 exome AF: 0.00116 AC: 1695 AN: 1458776 Hom.: 1 Cov.: 31 AF XY: 0.00110 AC XY: 801 AN XY: 725660

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000405

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000789

Gnomad4 NFE exome AF: 0.00142

Gnomad4 OTH exome AF: 0.000632

GnomAD4 genome AF: 0.000748 AC: 114 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.000685 AC XY: 51 AN XY: 74496

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000921 Hom.: 0

Bravo AF: 0.000680

ESP6500AA AF: 0.000247 AC: 1

ESP6500EA AF: 0.000838 AC: 7

ExAC AF: 0.000648 AC: 78

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.463G>A (p.D155N) alteration is located in exon 7 (coding exon 5) of the OGFOD2 gene. This alteration results from a G to A substitution at nucleotide position 463, causing the aspartic acid (D) at amino acid position 155 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	.;.;.;T;.;.;.;.;T;T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.;.;.;.;.;.;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.024	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.4	.;.;.;.;.;.;.;.;M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.080	T;D;D;D;D;D;D;D;T;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.;D;.
Vest4		0.86
MVP		0.78
MPC		0.25
ClinPred		0.095	T
GERP RS		5.4
Varity_R		0.41
gMVP		0.82

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: rs200470247; hg19: chr12-123463411; COSMIC: COSV54897818; COSMIC: COSV54897818;