10-98385025-C-T

Position:

• chr10-98385025-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032709.3(PYROXD2):​c.1597G>A​(p.Ala533Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,613,086 control chromosomes in the GnomAD database, including 89,731 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (9303 hom., cov: 32)
  • Exomes 𝑓: 0.32 (80428 hom.)
• Consequence: PYROXD2 NM_032709.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.990

Genes affected

PYROXD2 (HGNC:23517): (pyridine nucleotide-disulphide oxidoreductase domain 2) Predicted to enable oxidoreductase activity. Involved in mitochondrion organization. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.484853E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYROXD2	NM_032709.3	c.1597G>A	p.Ala533Thr	missense_variant	15/16	ENST00000370575.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYROXD2	ENST00000370575.5	c.1597G>A	p.Ala533Thr	missense_variant	15/16	1	NM_032709.3	P1
PYROXD2	ENST00000483923.5	n.2483G>A		non_coding_transcript_exon_variant	14/15	1

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52079 AN: 151760 Hom.: 9297 Cov.: 32

Gnomad AFR AF: 0.371

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.540

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.312

GnomAD3 exomes AF: 0.371 AC: 92941 AN: 250280 Hom.: 18500 AF XY: 0.372 AC XY: 50299 AN XY: 135332

Gnomad AFR exome AF: 0.371

Gnomad AMR exome AF: 0.499

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.417

Gnomad SAS exome AF: 0.527

Gnomad FIN exome AF: 0.287

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.323 AC: 472436 AN: 1461208 Hom.: 80428 Cov.: 36 AF XY: 0.328 AC XY: 238739 AN XY: 726862

Gnomad4 AFR exome AF: 0.371

Gnomad4 AMR exome AF: 0.488

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.418

Gnomad4 SAS exome AF: 0.528

Gnomad4 FIN exome AF: 0.286

Gnomad4 NFE exome AF: 0.296

Gnomad4 OTH exome AF: 0.337

GnomAD4 genome AF: 0.343 AC: 52108 AN: 151878 Hom.: 9303 Cov.: 32 AF XY: 0.349 AC XY: 25895 AN XY: 74240

Gnomad4 AFR AF: 0.371

Gnomad4 AMR AF: 0.417

Gnomad4 ASJ AF: 0.359

Gnomad4 EAS AF: 0.424

Gnomad4 SAS AF: 0.539

Gnomad4 FIN AF: 0.291

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.310

Alfa AF: 0.313 Hom.: 18879

Bravo AF: 0.351

TwinsUK AF: 0.294 AC: 1090

ALSPAC AF: 0.307 AC: 1182

ESP6500AA AF: 0.373 AC: 1642

ESP6500EA AF: 0.303 AC: 2610

ExAC AF: 0.369 AC: 44853

Asia WGS AF: 0.463 AC: 1606 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.91
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.00075	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.94	L
MutationTaster	Benign	0.000056	P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.056
Sift	Benign	0.64	T
Sift4G	Benign	0.57	T
Polyphen		0.12	B
Vest4		0.039
MPC		0.033
ClinPred		0.014	T
GERP RS		5.2
Varity_R		0.075
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2296441; hg19: chr10-100144782; COSMIC: COSV65329761; COSMIC: COSV65329761;