rs2870984

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_016335.6(PRODH):c.1397C>T(p.Thr466Met) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T466K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 1 hom., cov: 5)

Exomes 𝑓: 0.0048 ( 26 hom. )

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:3O:1

Conservation

PhyloP100: 4.62

Publications

17 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011515439).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00372 (104/27954) while in subpopulation SAS AF = 0.0143 (11/768). AF 95% confidence interval is 0.00803. There are 1 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 5. 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 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.1397C>T	p.Thr466Met	missense_variant	Exon 11 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.1073C>T	p.Thr358Met	missense_variant	Exon 11 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.1073C>T	p.Thr358Met	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.1397C>T	p.Thr466Met	missense_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+7318G>A		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.00370

AC:

103

AN:

27870

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00365

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00381

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.0108

Gnomad SAS

AF:

0.0132

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00943

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.00272

GnomAD2 exomes

AF:

0.00463

AC:

1160

AN:

250538

AF XY:

0.00481

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.00351

Gnomad ASJ exome

AF:

0.00917

Gnomad EAS exome

AF:

0.0144

Gnomad FIN exome

AF:

0.00148

Gnomad NFE exome

AF:

0.00253

Gnomad OTH exome

AF:

0.00522

GnomAD4 exome

AF:

0.00481

AC:

929

AN:

193086

Hom.:

Cov.:

AF XY:

0.00490

AC XY:

500

AN XY:

102144

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

7936

American (AMR)

AF:

0.00378

AC:

AN:

8988

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

AN:

6254

East Asian (EAS)

AF:

0.0173

AC:

406

AN:

23408

South Asian (SAS)

AF:

0.00580

AC:

122

AN:

21032

European-Finnish (FIN)

AF:

0.000718

AC:

AN:

11136

Middle Eastern (MID)

AF:

0.00792

AC:

AN:

1010

European-Non Finnish (NFE)

AF:

0.00203

AC:

207

AN:

101762

Other (OTH)

AF:

0.00519

AC:

AN:

11560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

103

137

171

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:

0.00372

AC:

104

AN:

27954

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

AN XY:

12788

show subpopulations

African (AFR)

AF:

0.00363

AC:

AN:

9654

American (AMR)

AF:

0.00379

AC:

AN:

2640

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

AN:

750

East Asian (EAS)

AF:

0.0109

AC:

AN:

1198

South Asian (SAS)

AF:

0.0143

AC:

AN:

768

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

1420

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00193

AC:

AN:

10892

Other (OTH)

AF:

0.00258

AC:

AN:

388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.00292

Hom.:

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00573

AC:

696

EpiCase

AF:

0.00393

EpiControl

AF:

0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Pathogenic:2Benign:1

Jan 06, 2017

Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intellectual disability; epilepsy; schizophrenia -

Oct 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PRODH: BS1, BS2 -

Jul 15, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Proline dehydrogenase deficiency;C1833247:Schizophrenia 4

Uncertain:1

Jun 20, 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

Oct 01, 2007

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

Benign

0.14

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;.;.;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.95

D;.;D;.

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.72

PhyloP100

4.6

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.5

.;D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.010

.;D;D;D

Sift4G

Uncertain

0.017

D;D;D;D

Polyphen

0.85

.;P;P;.

Vest4

0.45

MVP

0.040

MPC

0.39

ClinPred

0.078

GERP RS

3.1

gMVP

0.62

Mutation Taster

=92/8

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over