rs2238731

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.1279G>A(p.Val427Met) 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 0.030 ( 4 hom., cov: 2)

Exomes 𝑓: 0.036 ( 394 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: 0.286

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030622482).

BP6

Variant 22-18918464-C-T is Benign according to our data. Variant chr22-18918464-C-T is described in ClinVar as Benign. ClinVar VariationId is 459909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0996 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRODH	NM_016335.6 link	c.1279G>A	p.Val427Met	missense_variant	Exon 11 of 14	ENST00000357068.11	NP_057419.5	O43272
PRODH	NM_001195226.2 link	c.955G>A	p.Val319Met	missense_variant	Exon 11 of 14		NP_001182155.2	O43272
PRODH	NM_001368250.2 link	c.955G>A	p.Val319Met	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.1279G>A	p.Val427Met	missense_variant	Exon 11 of 14	1	NM_016335.6	ENSP00000349577.6		O43272
ENSG00000283809	ENST00000638240.1 link	c.513+7436C>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1		A0A1W2PRQ8

Frequencies

GnomAD3 genomes

AF:

0.0307

AC:

120

AN:

3904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0417

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0527

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0909

Gnomad SAS

AF:

0.00385

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.0109

GnomAD2 exomes

AF:

0.0384

AC:

9422

AN:

245360

AF XY:

0.0330

show subpopulations

Gnomad AFR exome

AF:

0.0779

Gnomad AMR exome

AF:

0.0941

Gnomad ASJ exome

AF:

0.0134

Gnomad EAS exome

AF:

0.134

Gnomad FIN exome

AF:

0.00295

Gnomad NFE exome

AF:

0.0170

Gnomad OTH exome

AF:

0.0279

GnomAD4 exome

AF:

0.0357

AC:

5726

AN:

160352

Hom.:

394

Cov.:

AF XY:

0.0331

AC XY:

2826

AN XY:

85352

show subpopulations

African (AFR)

AF:

0.0738

AC:

529

AN:

7168

American (AMR)

AF:

0.0904

AC:

729

AN:

8064

Ashkenazi Jewish (ASJ)

AF:

0.0140

AC:

AN:

5226

East Asian (EAS)

AF:

0.104

AC:

1847

AN:

17838

South Asian (SAS)

AF:

0.0109

AC:

240

AN:

21968

European-Finnish (FIN)

AF:

0.00501

AC:

AN:

7384

Middle Eastern (MID)

AF:

0.0175

AC:

AN:

856

European-Non Finnish (NFE)

AF:

0.0230

AC:

1897

AN:

82340

Other (OTH)

AF:

0.0378

AC:

359

AN:

9508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

205

411

616

822

1027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.0302

AC:

118

AN:

3912

Hom.:

Cov.:

AF XY:

0.0329

AC XY:

AN XY:

1796

show subpopulations

African (AFR)

AF:

0.0412

AC:

AN:

1166

American (AMR)

AF:

0.0508

AC:

AN:

472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.0872

AC:

AN:

344

South Asian (SAS)

AF:

0.00382

AC:

AN:

262

European-Finnish (FIN)

AF:

0.00

AC:

AN:

162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0101

AC:

AN:

1284

Other (OTH)

AF:

0.0208

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.0227

Hom.:

142

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0184

AC:

ESP6500AA

AF:

0.0795

AC:

350

ESP6500EA

AF:

0.0145

AC:

125

ExAC

AF:

0.0362

AC:

4393

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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: 23462603, 15662599, 24842239, 22090377) -

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

0.072

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.67

CADD

Benign

6.3

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0068

T;.;.;T

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.90

D;.;D;.

MetaRNN

Benign

0.0031

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

0.29

PrimateAI

Benign

0.35

PROVEAN

Benign

0.56

.;N;N;N

REVEL

Benign

0.037

Sift

Benign

0.50

.;T;T;T

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.35

.;B;B;.

Vest4

0.074

MPC

0.30

ClinPred

0.0020

GERP RS

-1.1

gMVP

0.59

Mutation Taster

=98/2

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