rs148375080

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_016335.6(PRODH):c.650G>A(p.Arg217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict 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. R217S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.092 ( 11 hom., cov: 0)

Exomes 𝑓: 0.11 ( 1681 hom. )

Failed GnomAD Quality Control

Consequence

PRODH
NM_016335.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0210

Publications

9 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011050582).

BP6

Variant 22-18925068-C-T is Benign according to our data. Variant chr22-18925068-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547846.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PRODH	NM_016335.6 link	c.650G>A	p.Arg217His	missense_variant	Exon 4 of 14	ENST00000357068.11	NP_057419.5
PRODH	NM_001195226.2 link	c.326G>A	p.Arg109His	missense_variant	Exon 4 of 14		NP_001182155.2
PRODH	NM_001368250.2 link	c.326G>A	p.Arg109His	missense_variant	Exon 4 of 14		NP_001355179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRODH	ENST00000357068.11 link	c.650G>A	p.Arg217His	missense_variant	Exon 4 of 14	1	NM_016335.6	ENSP00000349577.6
ENSG00000283809	ENST00000638240.1 link	c.513+14040C>T		intron_variant	Intron 4 of 5	5		ENSP00000492446.1

Frequencies

GnomAD3 genomes

AF:

0.0922

AC:

AN:

282

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMR

AF:

0.0714

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.104

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00472

AC:

1185

AN:

251136

AF XY:

0.00462

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000926

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0137

Gnomad NFE exome

AF:

0.00659

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.112

AC:

3477

AN:

31000

Hom.:

1681

Cov.:

AF XY:

0.105

AC XY:

1793

AN XY:

16996

show subpopulations

African (AFR)

AF:

0.0359

AC:

AN:

334

American (AMR)

AF:

0.0203

AC:

AN:

1676

Ashkenazi Jewish (ASJ)

AF:

0.0417

AC:

AN:

432

East Asian (EAS)

AF:

0.00

AC:

AN:

1370

South Asian (SAS)

AF:

0.0438

AC:

247

AN:

5636

European-Finnish (FIN)

AF:

0.156

AC:

446

AN:

2850

Middle Eastern (MID)

AF:

0.125

AC:

AN:

136

European-Non Finnish (NFE)

AF:

0.150

AC:

2539

AN:

16892

Other (OTH)

AF:

0.0980

AC:

164

AN:

1674

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0922

AC:

AN:

282

Hom.:

Cov.:

AF XY:

0.0846

AC XY:

AN XY:

130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.0714

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.150

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.104

AC:

AN:

144

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00598

Hom.:

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00445

AC:

540

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Proline dehydrogenase deficiency

Uncertain:1Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PRODH: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.024

T;.;.;T;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.077

LIST_S2

Uncertain

0.88

D;.;T;.;T

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-0.93

PhyloP100

0.021

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.3

.;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.12

.;T;T;T;T

Sift4G

Benign

0.24

T;T;T;T;T

Polyphen

0.0060

.;B;B;.;.

Vest4

0.052

MVP

0.14

MPC

0.34

ClinPred

0.010

GERP RS

-2.2

gMVP

0.29

Mutation Taster

=98/2

polymorphism

(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