10-98388419-A-G

Variant names:

• chr10-98388419-A-G
• rs2147896
• NM_032709.3:c.1382T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032709.3(PYROXD2):​c.1382T>C​(p.Met461Thr) variant causes a missense change. The variant allele was found at a frequency of 0.401 in 1,612,284 control chromosomes in the GnomAD database, including 140,579 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M461R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.51 (22292 hom., cov: 28)
  • Exomes 𝑓: 0.39 (118287 hom.)
• Consequence: PYROXD2 NM_032709.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.57
• Publications: 73 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.219642E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032709.3. 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
	PYROXD2	NM_032709.3	MANE Select	c.1382T>C	p.Met461Thr	missense	Exon 13 of 16	NP_116098.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYROXD2	ENST00000370575.5	TSL:1 MANE Select	c.1382T>C	p.Met461Thr	missense	Exon 13 of 16	ENSP00000359607.4
	PYROXD2	ENST00000483923.5	TSL:1	n.2334-1112T>C		intron	N/A
	PYROXD2	ENST00000906254.1		c.1526T>C	p.Met509Thr	missense	Exon 13 of 16	ENSP00000576313.1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77165 AN: 151068 Hom.: 22235 Cov.: 28

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.474

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.440

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.468

GnomAD2 exomes AF: 0.471 AC: 117642 AN: 249984 AF XY: 0.458

Gnomad AFR exome AF: 0.788

Gnomad AMR exome AF: 0.628

Gnomad ASJ exome AF: 0.466

Gnomad EAS exome AF: 0.557

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.433

GnomAD4 exome AF: 0.389 AC: 568821 AN: 1461098 Hom.: 118287 Cov.: 38 AF XY: 0.391 AC XY: 284504 AN XY: 726794

African (AFR) AF: 0.796 AC: 26647 AN: 33474

American (AMR) AF: 0.617 AC: 27564 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 12065 AN: 26122

East Asian (EAS) AF: 0.535 AC: 21219 AN: 39686

South Asian (SAS) AF: 0.526 AC: 45309 AN: 86178

European-Finnish (FIN) AF: 0.427 AC: 22791 AN: 53318

Middle Eastern (MID) AF: 0.461 AC: 2660 AN: 5768

European-Non Finnish (NFE) AF: 0.346 AC: 384690 AN: 1111528

Other (OTH) AF: 0.429 AC: 25876 AN: 60374

GnomAD4 genome AF: 0.511 AC: 77273 AN: 151186 Hom.: 22292 Cov.: 28 AF XY: 0.518 AC XY: 38250 AN XY: 73816

African (AFR) AF: 0.781 AC: 32100 AN: 41100

American (AMR) AF: 0.545 AC: 8288 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 1641 AN: 3464

East Asian (EAS) AF: 0.558 AC: 2857 AN: 5120

South Asian (SAS) AF: 0.534 AC: 2527 AN: 4730

European-Finnish (FIN) AF: 0.440 AC: 4596 AN: 10442

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23815 AN: 67828

Other (OTH) AF: 0.465 AC: 974 AN: 2096

Alfa AF: 0.407 Hom.: 65037

Bravo AF: 0.530

TwinsUK AF: 0.338 AC: 1254

ALSPAC AF: 0.356 AC: 1373

ESP6500AA AF: 0.767 AC: 3380

ESP6500EA AF: 0.358 AC: 3079

ExAC AF: 0.469 AC: 56932

Asia WGS AF: 0.567 AC: 1968 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-2.6	N
PhyloP100		6.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	5.0	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.078
MPC		0.036
ClinPred		0.0055	T
GERP RS		4.9
Varity_R		0.14
gMVP		0.39
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2147896; hg19: chr10-100148176; COSMIC: COSV65329770;