dbSNP rs2904551: PRODH:p.Leu441Pro (chr22-18918421-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 6P and 6B. PS3PP3PP5BP4BS1_SupportingBS2

The NM_016335.6(PRODH):c.1322T>C(p.Leu441Pro) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000490742: Functional studies show that the L441P variant leads to reduced stability of proline oxidase and significant reduction in its activity (Bender et al., 2005)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L441V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 3)

Exomes 𝑓: 0.0039 ( 50 hom. )

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:10O:1

Conservation

PhyloP100: 6.87

Publications

29 publications found

Variant links:

Genes affected

PRODH (HGNC:9453): (proline dehydrogenase 1) This gene encodes a mitochondrial protein that catalyzes the first step in proline degradation. Mutations in this gene are associated with hyperprolinemia type 1 and susceptibility to schizophrenia 4 (SCZD4). This gene is located on chromosome 22q11.21, a region which has also been associated with the contiguous gene deletion syndromes, DiGeorge and CATCH22. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2010]

PRODH Gene-Disease associations (from GenCC):

hyperprolinemia type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine, Orphanet

PRODH links:

ENSG00000283809 (HGNC:):

ENSG00000283809 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000490742: Functional studies show that the L441P variant leads to reduced stability of proline oxidase and significant reduction in its activity (Bender et al., 2005).; SCV003689836: Functional studies demonstrate that this alteration results in a severe reduction of proline oxidase (POX) activity and reduced stability (Zhang, 2004; Bender, 2005).; SCV005417289: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 22-18918421-A-G is Pathogenic according to our data. Variant chr22-18918421-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4008.

BP4

Computational evidence support a benign effect (MetaRNN=0.06687951). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00253 (29/11484) while in subpopulation EAS AF = 0.00446 (3/672). AF 95% confidence interval is 0.0015. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 3. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 50 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016335.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRODH	NM_016335.6	MANE Select	c.1322T>C	p.Leu441Pro	missense	Exon 11 of 14	NP_057419.5
PRODH	NM_001195226.2		c.998T>C	p.Leu333Pro	missense	Exon 11 of 14	NP_001182155.2	O43272-2
PRODH	NM_001368250.2		c.998T>C	p.Leu333Pro	missense	Exon 11 of 14	NP_001355179.2	E7EQL6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRODH	ENST00000357068.11	TSL:1 MANE Select	c.1322T>C	p.Leu441Pro	missense	Exon 11 of 14	ENSP00000349577.6	O43272-4
PRODH	ENST00000610940.4	TSL:1	c.1322T>C	p.Leu441Pro	missense	Exon 12 of 15	ENSP00000480347.1	O43272-4
PRODH	ENST00000334029.6	TSL:1	c.998T>C	p.Leu333Pro	missense	Exon 11 of 14	ENSP00000334726.2	O43272-2

Frequencies

GnomAD3 genomes

AF:

0.00253

AC:

AN:

11466

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.0476

Gnomad AMR

AF:

0.00333

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00440

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00146

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00191

Gnomad OTH

AF:

0.00521

GnomAD2 exomes

AF:

0.00521

AC:

1303

AN:

249888

AF XY:

0.00507

show subpopulations

Gnomad AFR exome

AF:

0.00472

Gnomad AMR exome

AF:

0.00661

Gnomad ASJ exome

AF:

0.00550

Gnomad EAS exome

AF:

0.00597

Gnomad FIN exome

AF:

0.00436

Gnomad NFE exome

AF:

0.00496

Gnomad OTH exome

AF:

0.00737

GnomAD4 exome

AF:

0.00392

AC:

748

AN:

190684

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

388

AN XY:

100218

show subpopulations

African (AFR)

AF:

0.00403

AC:

AN:

8196

American (AMR)

AF:

0.00546

AC:

AN:

8788

Ashkenazi Jewish (ASJ)

AF:

0.00418

AC:

AN:

6462

East Asian (EAS)

AF:

0.00440

AC:

105

AN:

23840

South Asian (SAS)

AF:

0.00335

AC:

AN:

19700

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

10238

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

1014

European-Non Finnish (NFE)

AF:

0.00380

AC:

383

AN:

100794

Other (OTH)

AF:

0.00395

AC:

AN:

11652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

104

130

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:

0.00253

AC:

AN:

11484

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

AN XY:

5078

show subpopulations

African (AFR)

AF:

0.00276

AC:

AN:

3620

American (AMR)

AF:

0.00333

AC:

AN:

1200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

306

East Asian (EAS)

AF:

0.00446

AC:

AN:

672

South Asian (SAS)

AF:

0.00

AC:

AN:

502

European-Finnish (FIN)

AF:

0.00146

AC:

AN:

686

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00191

AC:

AN:

4188

Other (OTH)

AF:

0.00495

AC:

AN:

202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.00478

Hom.:

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00571

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.00674

AC:

ExAC

AF:

0.00575

AC:

698

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Proline dehydrogenase deficiency (9)

not provided (4)

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4 (2)

Inborn genetic diseases (1)

not specified (1)

Schizophrenia 4 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.067

MetaSVM

Uncertain

0.33

PhyloP100

6.9

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.66

Vest4

0.99

MVP

0.71

MPC

0.91

ClinPred

0.11

GERP RS

4.5

gMVP

0.98

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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