1-39770319-C-G

Variant names:

• chr1-39770319-C-G
• rs571438719
• NM_022120.2:c.937G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_022120.2(OXCT2):​c.937G>C​(p.Gly313Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,034 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. G313C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 19)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OXCT2 NM_022120.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77
• Publications: 0 publications found

Genes affected

OXCT2 (HGNC:18606): (3-oxoacid CoA-transferase 2) The protein encoded by this gene catalyzes the transfer of a CoA group from succinate to acetoacetate and is an important enzyme in ketone body catabolism. The encoded protein localizes to the mitochondrion. This gene is intronless, and a pseudogene of this gene is located elsewhere on chromosome 1. [provided by RefSeq, Aug 2016]

BMP8B (HGNC:1075): (bone morphogenetic protein 8b) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The encoded protein stimulates thermogenesis in brown adipose tissue. Expression of this gene may be downregulated in pancreatic cancer. This gene may have arose from a gene duplication event and its gene duplicate is also present on chromosome 1. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022120.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OXCT2	NM_022120.2	MANE Select	c.937G>C	p.Gly313Arg	missense	Exon 1 of 1	NP_071403.1	Q9BYC2
	BMP8B	NM_001720.5	MANE Select	c.673+3989G>C		intron	N/A	NP_001711.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OXCT2	ENST00000327582.5	TSL:6 MANE Select	c.937G>C	p.Gly313Arg	missense	Exon 1 of 1	ENSP00000361914.1	Q9BYC2
	BMP8B	ENST00000372827.8	TSL:1 MANE Select	c.673+3989G>C		intron	N/A	ENSP00000361915.3	P34820-1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452034 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722080

African (AFR) AF: 0.00 AC: 0 AN: 32448

American (AMR) AF: 0.00 AC: 0 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25422

East Asian (EAS) AF: 0.00 AC: 0 AN: 39298

South Asian (SAS) AF: 0.00 AC: 0 AN: 85374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5400

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107222

Other (OTH) AF: 0.00 AC: 0 AN: 59986

GnomAD4 genome Cov.: 19

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	0.080
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.65	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		2.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.86		Gain of MoRF binding (P = 0.0545)
MVP		0.99
ClinPred		1.0	D
GERP RS		1.6
Varity_R		0.87
gMVP		0.91
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs571438719; hg19: chr1-40235991;