NM_016335.6:c.1765C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2

The NM_016335.6(PRODH):c.1765C>T(p.Arg589Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 2 hom., cov: 0)

Exomes 𝑓: 0.000012 ( 3 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.754

Publications

0 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 links:

ENSG00000283809 (HGNC:):

ENSG00000283809 links:

DGCR6 (HGNC:2846): (DiGeorge syndrome critical region gene 6) DiGeorge syndrome, and more widely, the CATCH 22 syndrome, are associated with microdeletions in chromosomal region 22q11.2. The product of this gene shares homology with the Drosophila melanogaster gonadal protein, which participates in gonadal and germ cell development, and with the gamma-1 subunit of human laminin. This gene is a candidate for involvement in DiGeorge syndrome pathology and in schizophrenia. [provided by RefSeq, Nov 2008]

DGCR6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.748

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000135 (4/29592) while in subpopulation SAS AF = 0.00274 (2/730). AF 95% confidence interval is 0.000487. There are 2 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.1765C>T	p.Arg589Trp	missense_variant	Exon 14 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.1441C>T	p.Arg481Trp	missense_variant	Exon 14 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.1441C>T	p.Arg481Trp	missense_variant	Exon 14 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 link	c.1765C>T	p.Arg589Trp	missense_variant	Exon 14 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+2185G>A		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.000136

AC:

AN:

29518

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00275

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

157048

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000122

AC:

AN:

490868

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

241216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19208

American (AMR)

AF:

0.000285

AC:

AN:

14022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8516

East Asian (EAS)

AF:

0.00

AC:

AN:

11388

South Asian (SAS)

AF:

0.00

AC:

AN:

26578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17764

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2282

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

369748

Other (OTH)

AF:

0.0000936

AC:

AN:

21362

Age Distribution

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:

0.000135

AC:

AN:

29592

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

AN XY:

14350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13990

American (AMR)

AF:

0.00

AC:

AN:

1982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

426

East Asian (EAS)

AF:

0.00

AC:

AN:

578

South Asian (SAS)

AF:

0.00274

AC:

AN:

730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

9720

Other (OTH)

AF:

0.00

AC:

AN:

350

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000189

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 25, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1765C>T (p.R589W) alteration is located in exon 15 (coding exon 14) of the PRODH gene. This alteration results from a C to T substitution at nucleotide position 1765, causing the arginine (R) at amino acid position 589 to be replaced by a tryptophan (W). The p.R589W alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4

Uncertain:1

May 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

D;.;.;D

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.82

T;.;T;.

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Benign

-0.48

PhyloP100

0.75

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.7

.;D;D;D

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

.;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.52

MutPred

0.76

Loss of disorder (P = 5e-04);.;.;Loss of disorder (P = 5e-04);

MVP

0.22

MPC

0.85

ClinPred

0.99

GERP RS

-0.84

gMVP

0.95

Mutation Taster

=33/67

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over