rs3970559

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016335.6(PRODH):c.1357C>T(p.Arg453Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R453P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.018 ( 12 hom., cov: 4)

Exomes 𝑓: 0.013 ( 181 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:3O:1

Conservation

PhyloP100: 2.03

Publications

19 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: ClinGen, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)

PRODH links:

ENSG00000283809 (HGNC:):

ENSG00000283809 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012216002).

BP6

Variant 22-18918386-G-A is Benign according to our data. Variant chr22-18918386-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 4006.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0125 (2640/211074) while in subpopulation AFR AF = 0.0384 (329/8564). AF 95% confidence interval is 0.035. There are 181 homozygotes in GnomAdExome4. There are 1348 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 181 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.1357C>T	p.Arg453Cys	missense_variant	Exon 11 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.1033C>T	p.Arg345Cys	missense_variant	Exon 11 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.1033C>T	p.Arg345Cys	missense_variant	Exon 11 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 link	c.1357C>T	p.Arg453Cys	missense_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+7358G>A		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

332

AN:

18570

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0310

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.0268

Gnomad ASJ

AF:

0.00602

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.0113

Gnomad FIN

AF:

0.00289

Gnomad MID

AF:

0.0111

Gnomad NFE

AF:

0.00754

Gnomad OTH

AF:

0.0155

GnomAD2 exomes

AF:

0.0108

AC:

2704

AN:

249400

AF XY:

0.0106

show subpopulations

Gnomad AFR exome

AF:

0.0273

Gnomad AMR exome

AF:

0.0169

Gnomad ASJ exome

AF:

0.00737

Gnomad EAS exome

AF:

0.0137

Gnomad FIN exome

AF:

0.00320

Gnomad NFE exome

AF:

0.00802

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.0125

AC:

2640

AN:

211074

Hom.:

181

Cov.:

AF XY:

0.0121

AC XY:

1348

AN XY:

111248

show subpopulations

African (AFR)

AF:

0.0384

AC:

329

AN:

8564

American (AMR)

AF:

0.0173

AC:

167

AN:

9642

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

108

AN:

7036

East Asian (EAS)

AF:

0.0135

AC:

342

AN:

25290

South Asian (SAS)

AF:

0.00902

AC:

200

AN:

22176

European-Finnish (FIN)

AF:

0.00240

AC:

AN:

12082

Middle Eastern (MID)

AF:

0.0128

AC:

AN:

1098

European-Non Finnish (NFE)

AF:

0.0112

AC:

1258

AN:

112378

Other (OTH)

AF:

0.0151

AC:

193

AN:

12808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

170

255

340

425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0180

AC:

335

AN:

18618

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

152

AN XY:

8320

show subpopulations

African (AFR)

AF:

0.0314

AC:

193

AN:

6156

American (AMR)

AF:

0.0266

AC:

AN:

1916

Ashkenazi Jewish (ASJ)

AF:

0.00602

AC:

AN:

498

East Asian (EAS)

AF:

0.0161

AC:

AN:

930

South Asian (SAS)

AF:

0.0112

AC:

AN:

624

European-Finnish (FIN)

AF:

0.00289

AC:

AN:

1038

Middle Eastern (MID)

AF:

0.0122

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00755

AC:

AN:

7024

Other (OTH)

AF:

0.0146

AC:

AN:

274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0124

Hom.:

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.0168

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.0125

AC:

1516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Pathogenic:1Benign:1

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Benign:2

Apr 18, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 3% in African population, >1% in most other populations. In addition, no clearly associated clinical manifestations -

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4

Uncertain:1

Feb 24, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Schizophrenia 4

Other:1

Mar 01, 2005

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;.;.;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.078

FATHMM_MKL

Benign

0.67

LIST_S2

Uncertain

0.89

D;.;D;.

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.53

PhyloP100

2.0

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-7.1

.;D;D;D

REVEL

Benign

0.27

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Uncertain

0.014

D;D;D;D

Polyphen

0.99

.;D;D;.

Vest4

0.32

MPC

1.1

ClinPred

0.14

GERP RS

3.2

gMVP

0.82

Mutation Taster

=91/9

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over