rs2904552

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_016335.6(PRODH):c.1292G>A(p.Arg431His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.051 ( 15 hom., cov: 2)

Exomes 𝑓: 0.10 ( 2136 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:4O:1

Conservation

PhyloP100: 1.45

Publications

26 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036971867).

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PRODH	NM_016335.6 link	c.1292G>A	p.Arg431His	missense_variant	Exon 11 of 14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2 link	c.968G>A	p.Arg323His	missense_variant	Exon 11 of 14		NP_001182155.2
PRODH	NM_001368250.2 link	c.968G>A	p.Arg323His	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.1292G>A	p.Arg431His	missense_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1 link	c.513+7423C>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1

Frequencies

GnomAD3 genomes

AF:

0.0508

AC:

283

AN:

5570

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0213

Gnomad AMI

AF:

0.500

Gnomad AMR

AF:

0.0466

Gnomad ASJ

AF:

0.0789

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0269

Gnomad FIN

AF:

0.0414

Gnomad MID

AF:

0.0370

Gnomad NFE

AF:

0.0955

Gnomad OTH

AF:

0.0660

GnomAD2 exomes

AF:

0.0723

AC:

17881

AN:

247476

AF XY:

0.0738

show subpopulations

Gnomad AFR exome

AF:

0.0325

Gnomad AMR exome

AF:

0.0476

Gnomad ASJ exome

AF:

0.114

Gnomad EAS exome

AF:

0.000656

Gnomad FIN exome

AF:

0.0477

Gnomad NFE exome

AF:

0.105

Gnomad OTH exome

AF:

0.0829

GnomAD4 exome

AF:

0.103

AC:

17301

AN:

168500

Hom.:

2136

Cov.:

AF XY:

0.0995

AC XY:

8911

AN XY:

89530

show subpopulations

African (AFR)

AF:

0.0328

AC:

249

AN:

7580

American (AMR)

AF:

0.0685

AC:

563

AN:

8220

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

764

AN:

5534

East Asian (EAS)

AF:

0.000642

AC:

AN:

20260

South Asian (SAS)

AF:

0.0519

AC:

1079

AN:

20808

European-Finnish (FIN)

AF:

0.0682

AC:

552

AN:

8094

Middle Eastern (MID)

AF:

0.102

AC:

AN:

894

European-Non Finnish (NFE)

AF:

0.148

AC:

12857

AN:

86894

Other (OTH)

AF:

0.111

AC:

1133

AN:

10216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

568

1136

1704

2272

2840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.0509

AC:

284

AN:

5584

Hom.:

Cov.:

AF XY:

0.0496

AC XY:

123

AN XY:

2482

show subpopulations

African (AFR)

AF:

0.0216

AC:

AN:

1756

American (AMR)

AF:

0.0466

AC:

AN:

644

Ashkenazi Jewish (ASJ)

AF:

0.0789

AC:

AN:

114

East Asian (EAS)

AF:

0.00

AC:

AN:

462

South Asian (SAS)

AF:

0.0271

AC:

AN:

332

European-Finnish (FIN)

AF:

0.0414

AC:

AN:

266

Middle Eastern (MID)

AF:

0.0370

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0957

AC:

176

AN:

1840

Other (OTH)

AF:

0.0625

AC:

AN:

112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.0926

Hom.:

1111

TwinsUK

AF:

0.102

AC:

379

ALSPAC

AF:

0.112

AC:

431

ESP6500AA

AF:

0.0366

AC:

161

ESP6500EA

AF:

0.105

AC:

900

ExAC

AF:

0.0746

AC:

9050

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Pathogenic:1Uncertain:1Benign:2

Feb 03, 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

- -

Apr 29, 2022

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Schizophrenia 4

Pathogenic:1Other:1

Mar 01, 2005

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 13, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM3,â”¬Ã¡PP3,â”¬Ã¡PP5. -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4

Benign:1

Jan 31, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.083

T;.;.;T

Eigen

Benign

0.021

Eigen_PC

Benign

-0.030

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.89

D;.;D;.

MetaRNN

Benign

0.0037

T;T;T;T

MetaSVM

Benign

-1.2

PhyloP100

1.4

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.3

.;D;D;D

REVEL

Benign

0.14

Sift

Uncertain

0.0040

.;D;D;D

Sift4G

Uncertain

0.032

D;D;D;D

Polyphen

0.94

.;P;P;.

Vest4

0.16

MPC

0.44

ClinPred

0.033

GERP RS

1.2

gMVP

0.62

Mutation Taster

=97/3

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

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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