1-39769997-A-G

Variant names:

• chr1-39769997-A-G
• rs1363645953
• NM_022120.2:c.1259T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022120.2(OXCT2):​c.1259T>C​(p.Met420Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,367,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000072 (0 hom., cov: 19)
  • Exomes 𝑓: 0.0000044 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OXCT2 NM_022120.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1259T>C	p.Met420Thr	missense	Exon 1 of 1	NP_071403.1	Q9BYC2
	BMP8B	NM_001720.5	MANE Select	c.673+4311T>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.1259T>C	p.Met420Thr	missense	Exon 1 of 1	ENSP00000361914.1	Q9BYC2
	BMP8B	ENST00000372827.8	TSL:1 MANE Select	c.673+4311T>C		intron	N/A	ENSP00000361915.3	P34820-1

Frequencies

GnomAD3 genomes AF: 0.00000717 AC: 1 AN: 139466 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000705

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000439 AC: 6 AN: 1367836 Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1 AN XY: 673812

African (AFR) AF: 0.00 AC: 0 AN: 30802

American (AMR) AF: 0.00 AC: 0 AN: 34706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23898

East Asian (EAS) AF: 0.00 AC: 0 AN: 35950

South Asian (SAS) AF: 0.00 AC: 0 AN: 77610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45210

Middle Eastern (MID) AF: 0.000220 AC: 1 AN: 4536

European-Non Finnish (NFE) AF: 0.00000378 AC: 4 AN: 1058424

Other (OTH) AF: 0.0000176 AC: 1 AN: 56700

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000717 AC: 1 AN: 139466 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 67294

African (AFR) AF: 0.00 AC: 0 AN: 35726

American (AMR) AF: 0.0000705 AC: 1 AN: 14180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3274

East Asian (EAS) AF: 0.00 AC: 0 AN: 4610

South Asian (SAS) AF: 0.00 AC: 0 AN: 3874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65146

Other (OTH) AF: 0.00 AC: 0 AN: 1872

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		1.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.78		Loss of sheet (P = 0.0315)
MVP		1.0
ClinPred		1.0	D
GERP RS		2.4
Varity_R		0.65
gMVP		0.69
Mutation Taster		=71/29	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: rs1363645953; hg19: chr1-40235669;