22-18918329-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016335.6(PRODH):c.1414G>A(p.Ala472Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 108 hom., cov: 5)

Exomes 𝑓: 0.061 ( 746 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.110

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017911196).

BP6

Variant 22-18918329-C-T is Benign according to our data. Variant chr22-18918329-C-T is described in ClinVar as Benign. ClinVar VariationId is 1168804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.1414G>A	p.Ala472Thr	missense_variant	Exon 11 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.1090G>A	p.Ala364Thr	missense_variant	Exon 11 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.1090G>A	p.Ala364Thr	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.1414G>A	p.Ala472Thr	missense_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+7301C>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.0550

AC:

1661

AN:

30174

Hom.:

109

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0266

Gnomad AMI

AF:

0.141

Gnomad AMR

AF:

0.0621

Gnomad ASJ

AF:

0.106

Gnomad EAS

AF:

0.0236

Gnomad SAS

AF:

0.0294

Gnomad FIN

AF:

0.0752

Gnomad MID

AF:

0.0714

Gnomad NFE

AF:

0.0760

Gnomad OTH

AF:

0.0676

GnomAD2 exomes

AF:

0.0494

AC:

12348

AN:

250070

AF XY:

0.0491

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.0480

Gnomad ASJ exome

AF:

0.0693

Gnomad EAS exome

AF:

0.0233

Gnomad FIN exome

AF:

0.0552

Gnomad NFE exome

AF:

0.0558

Gnomad OTH exome

AF:

0.0694

GnomAD4 exome

AF:

0.0610

AC:

8552

AN:

140242

Hom.:

746

Cov.:

AF XY:

0.0605

AC XY:

4473

AN XY:

73976

show subpopulations

African (AFR)

AF:

0.0280

AC:

175

AN:

6248

American (AMR)

AF:

0.0548

AC:

359

AN:

6554

Ashkenazi Jewish (ASJ)

AF:

0.0832

AC:

382

AN:

4592

East Asian (EAS)

AF:

0.0319

AC:

590

AN:

18518

South Asian (SAS)

AF:

0.0305

AC:

415

AN:

13602

European-Finnish (FIN)

AF:

0.0746

AC:

614

AN:

8234

Middle Eastern (MID)

AF:

0.0861

AC:

AN:

778

European-Non Finnish (NFE)

AF:

0.0736

AC:

5387

AN:

73204

Other (OTH)

AF:

0.0661

AC:

563

AN:

8512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

305

610

915

1220

1525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.0549

AC:

1661

AN:

30272

Hom.:

108

Cov.:

AF XY:

0.0547

AC XY:

763

AN XY:

13942

show subpopulations

African (AFR)

AF:

0.0265

AC:

281

AN:

10604

American (AMR)

AF:

0.0617

AC:

168

AN:

2724

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

AN:

830

East Asian (EAS)

AF:

0.0237

AC:

AN:

1268

South Asian (SAS)

AF:

0.0278

AC:

AN:

790

European-Finnish (FIN)

AF:

0.0752

AC:

114

AN:

1516

Middle Eastern (MID)

AF:

0.0784

AC:

AN:

102

European-Non Finnish (NFE)

AF:

0.0760

AC:

903

AN:

11884

Other (OTH)

AF:

0.0628

AC:

AN:

398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

132

197

263

329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0521

Hom.:

197

TwinsUK

AF:

0.0434

AC:

161

ALSPAC

AF:

0.0441

AC:

170

ESP6500AA

AF:

0.0313

AC:

138

ESP6500EA

AF:

0.0601

AC:

517

ExAC

AF:

0.0504

AC:

6120

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 08, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22090377, 15662599, 23462603) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Proline dehydrogenase deficiency

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.72

CADD

Benign

9.3

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.022

T;.;.;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.39

T;.;T;.

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.11

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.91

.;N;N;N

REVEL

Benign

0.064

Sift

Benign

0.52

.;T;T;T

Sift4G

Benign

0.56

T;T;T;T

Polyphen

0.010

.;B;B;.

Vest4

0.091

MPC

0.27

ClinPred

0.0067

GERP RS

0.86

gMVP

0.40

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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