chr1-39769737-G-A

Position:

• chr1-39769737-G-A

Variant summary

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

The NM_022120.2(OXCT2):​c.1519C>T​(p.Pro507Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000745 in 1,610,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: OXCT2 NM_022120.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

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

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=0.021435052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OXCT2	NM_022120.2	c.1519C>T	p.Pro507Ser	missense_variant	1/1	ENST00000327582.5	NP_071403.1
BMP8B	NM_001720.5	c.673+4571C>T		intron_variant		ENST00000372827.8	NP_001711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OXCT2	ENST00000327582.5	c.1519C>T	p.Pro507Ser	missense_variant	1/1	6	NM_022120.2	ENSP00000361914.1
BMP8B	ENST00000372827.8	c.673+4571C>T		intron_variant		1	NM_001720.5	ENSP00000361915.3

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000690 AC: 171 AN: 247832 Hom.: 0 AF XY: 0.000657 AC XY: 88 AN XY: 133892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00117

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000720 AC: 1050 AN: 1458662 Hom.: 0 Cov.: 50 AF XY: 0.000770 AC XY: 559 AN XY: 725550

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.000858

Gnomad4 OTH exome AF: 0.000382

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74462

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00169 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000832 AC: 101

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

Jul 06, 2021

The c.1519C>T (p.P507S) alteration is located in exon 1 (coding exon 1) of the OXCT2 gene. This alteration results from a C to T substitution at nucleotide position 1519, causing the proline (P) at amino acid position 507 to be replaced by a serine (S). 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	Benign	0.098
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Benign	0.72
DEOGEN2	Benign	0.073	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.20
Sift	Benign	0.29	T
Sift4G	Benign	0.20	T
Polyphen		0.032	B
Vest4		0.27
MVP		0.92
ClinPred		0.055	T
GERP RS		1.6
Varity_R		0.090
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150126878; hg19: chr1-40235409; COSMIC: COSV59593301;