dbSNP rs145326227: PYROXD1:p.Gln28Lys (chr12-21437812-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_024854.5(PYROXD1):c.82C>A(p.Gln28Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000844 in 1,612,160 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 2 hom. )

Consequence

PYROXD1
NM_024854.5 missense, splice_region

Scores

Splicing: ADA: 0.0001540

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.13

Publications

0 publications found

Variant links:

Genes affected

PYROXD1 (HGNC:26162): (pyridine nucleotide-disulphide oxidoreductase domain 1) This gene encodes a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins that catalyze the pyridine nucleotide-dependent reduction of thiol residues in other proteins. The encoded protein belongs to the class I pyridine nucleotide-disulphide oxidoreductase family but lacks the C-terminal dimerization domain found in other family members and instead has a C-terminal nitrile reductase domain. It localizes to the nucleus and to striated sarcomeric compartments. Naturally occurring mutations in this gene cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. A pseudogene of this gene has been defined on chromosome 11. [provided by RefSeq, Apr 2017]

PYROXD1 Gene-Disease associations (from GenCC):

myofibrillar myopathy 8
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

PYROXD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0084551275).

BP6

Variant 12-21437812-C-A is Benign according to our data. Variant chr12-21437812-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1589002.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00019 (29/152372) while in subpopulation AFR AF = 0.000625 (26/41600). AF 95% confidence interval is 0.000438. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024854.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PYROXD1	NM_024854.5	MANE Select	c.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 12	NP_079130.2	Q8WU10-1
PYROXD1	NM_001350913.2		c.-622C>A		splice_region	Exon 1 of 11	NP_001337842.1
PYROXD1	NM_001350913.2		c.-622C>A		5_prime_UTR	Exon 1 of 11	NP_001337842.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 12	ENSP00000240651.9	Q8WU10-1
PYROXD1	ENST00000544970.5	TSL:1	n.82C>A		splice_region non_coding_transcript_exon	Exon 1 of 11	ENSP00000439106.1	B4DEW4
PYROXD1	ENST00000887643.1		c.82C>A	p.Gln28Lys	missense splice_region	Exon 1 of 12	ENSP00000557702.1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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

GnomAD2 exomes

AF:

0.000124

AC:

AN:

242640

AF XY:

0.0000834

show subpopulations

Gnomad AFR exome

AF:

0.00118

Gnomad AMR exome

AF:

0.000235

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000914

Gnomad OTH exome

AF:

0.000514

GnomAD4 exome

AF:

0.0000733

AC:

107

AN:

1459788

Hom.:

Cov.:

AF XY:

0.0000647

AC XY:

AN XY:

725982

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

33468

American (AMR)

AF:

0.000337

AC:

AN:

44524

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26022

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.0000934

AC:

AN:

85640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53078

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111398

Other (OTH)

AF:

0.000183

AC:

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000190

AC:

AN:

152372

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.000625

AC:

AN:

41600

American (AMR)

AF:

0.000196

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000336

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.069

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.79

M_CAP

Benign

0.028

MetaRNN

Benign

0.0085

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PhyloP100

1.1

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.4

REVEL

Benign

0.041

Sift

Benign

0.80

Sift4G

Benign

0.72

Polyphen

0.0010

Vest4

0.26

MVP

0.061

MPC

0.18

ClinPred

0.027

GERP RS

2.7

PromoterAI

0.11

Neutral

(source)

Varity_R

0.11

gMVP

0.72

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00015

dbscSNV1_RF

Benign

0.010

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over